Chapter 8
Drugs for Central
Nervous System
Disorders
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1
Learning Objectives
• Develop an understanding of the
physiologic processes that occur in
epilepsy.
• Classify seizures and the goals of their
therapy.
• Understand that specific drugs are
used in different classes of seizures.
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Learning Objectives
• Be familiar with Parkinson disease and
the drugs used in its treatment.
• Identify the drugs and goals of therapy
for attention-deficit disorders.
• Realize that some drugs may be used
for several disease states.
• Recognize drugs used to treat
Alzheimer disease.
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3
Epilepsy
• Common neurologic disorder with sudden
and recurring (paroxysmal) seizures
• Caused by abnormal electrical impulses in
the brain
• All epilepsy patients have seizures; not all
with seizures have epilepsy
• 1% to 2% have chronic epilepsy
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Seizures
• Disturbances of neuronal electrical activity
that interferes with normal brain function
• Behavior change patient not aware of
• Conscious periods may or may not lose
control over movement
• Loss of body control may affect one area
or entire body
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Convulsions
• Excessive firing of neurons can result
in a convulsion
– Involuntary contraction or series of
contractions of the voluntary muscles
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Causes of Seizures
• Imbalance of excitatory and inhibitory
neurotransmitters
– GABA: excitatory
– Glutamate: inhibitory
– Other neurotransmitters can be involved
• Enzymes control neurotransmitter levels
• Disruption in enzymes = disruption of
neurotransmitters
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Causes of Seizures
•
•
•
•
•
•
•
Alcohol or drug withdrawal
Epilepsy
High fever
Hypoglycemia, hyperglycemia
Infection (meningitis)
Neoplasm (brain tumor)
Trauma or injury (head, hematoma)
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Two Classes of Seizures
• Partial
– Simple partial
– Complex partial
• Generalized
–
–
–
–
Tonic-clonic (was called grand mal seizure)
Absence (was called petit mal seizure)
Myoclonic
Atonic
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Partial Seizures
• Localized in a specific area of the brain
• Almost always results from injury to
cerebral cortex
• Occurs in about 65% of people with
epilepsy
• Can progress to generalized seizures
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Two Classes of Partial
Seizures
• Simple Partial
– No loss of consciousness
– May have muscle twitching or sensory
hallucinations
• Complex Partial
– Impaired consciousness
– Confusion, blank stare, and postseizure
amnesia
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Generalized Seizures
• Involves both hemispheres of the brain, no
specific location
• Four types
• Tonic-Clonic
– Absence
– Myoclonic
– Atonic
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Tonic-Clonic Seizures
• Tonic: body becomes rigid, patient may
fall, lasts a minute or less
• Clonic: starts with muscle jerks, may be
accompanied by shallow breathing, loss of
bladder control, and excess salivation
– Lasts a few minutes
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Absence Seizures
• Interruption of activities by blank stare,
rotating eyes, uncontrolled facial
movements, rapid eye blinking, twitching
or jerking of an arm or leg
• No generalized convulsions
• Usually lasts 30 seconds or less
• Most prevalent first 10 years of life. 50% of
children have tonic-clonic as grow older
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Myoclonic Seizures
• Occurs with sudden, massive, brief
muscle jerks which may throw patient
down or nonmassive, quick jerks
• Consciousness is not lost
• Can occur during sleep
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Atonic Seizures
• Begins with sudden loss of muscle
tone and consciousness
• Patient may collapse, head drop, arm
or leg may go limp
• Lasts few seconds to a minute, then
patient can stand and walk again
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Status Epilepticus
• Continuous tonic-clonic seizures, with
or without return to consciousness
• Last at least 30 minutes
• High fever and lack of oxygen that
can cause brain damage or death
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Two Goals of Antiepileptic
Therapy
• Seizure control or lessen the
frequency
• Prevent emotional and behavioral
changes that may result from
seizures
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Antiepileptic Drug Therapy
• Different seizure types require different
drugs
• Start with monotherapy at low dose and
increase slowly over 3 to 4 weeks
• Medication must be maintained at steady
therapeutic levels
• If insufficient response, polytherapy can be
considered
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Antiepileptic Drug
Therapy
• Newer drugs are seizure-specific
• High potential for drug interactions
• Anticonvulsants have narrow therapeutic
ranges
• Minor dosage changes can result in loss of
seizure control or toxicity
• Prescribers often write for the brand name
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Drug List
Anticonvulsants
– carbamazepine (Epitol, Tegretol)
– clonazepam (Klonopin)
– diazepam (Valium)
– divalproex (Depakote)
– ethosuximide (Zarontin)
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Drug List
Anticonvulsants
– fosphyenytoin (Cerebyx)
– gabapentin (Neurontin)
– lamotrigine (Lamictal)
– levetiracetam (Keppra)
– lorazepam (Ativan)
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Drug List
Anticonvulsants
– oxcarbazepine (Trileptal)
– phenobarbital (Luminal Sodium)
– phenytoin (Dilantin)
– pregabalin (Lyrica)
– primidone (Mysoline)
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Drug List
Anticonvulsants
– tiagabine (Gabitrol)
– topiramate (Topamax)
– valproic acid (Depakene)
– zonisamide (Zonegran)
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Dispensing Issues of
Anticonvulsants
Warning!
• Prescribers often do not allow generic
drugs
• Pharmacy technicians watch for DAW
• If computer changes drug to generic,
technicians often change drug to brand
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carbamazepine (Epitol,
Tegretol)
• Effect on sodium channels which
may alter synaptic transmission
• Blood monitoring important
• Many interactions with other drugs
• Side effects can be serious
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clonazepam (Klonopin)
• Prophylaxis of seizures
• Depresses nerve transmission in the
motor cortex
• C-IV controlled substance
(benzodiazepine)
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gabapentin (Neurontin)
• Used as adjunct
• No significant drug interactions, welltolerated, easy to use
• Used for many other disorders,
particularly neuropathic pain
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Dispensing Issues of
Neurontin
Warning!
• Sound-alike drugs, but different
strengths
– Neurontin, usually 100 mg
– Noroxin (antibiotic), usually 400 mg
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lamotrigine (Lamictal)
• Add-on therapy for adults with partial
seizures
• Blocks sodium channels which
reduces neuron excitation
• Call physician immediately if rash
appears, do not discontinue abruptly
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Dispensing Issues of
Lamictal
Warning!
• Look-alike and sound-alike
– Lamictal
– Lamisil (terbinafine), antifungal
– Lomotil (diphenoxylate-atropine),
diarrhea
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Dispensing Issues of
Lamictal
Warning!
• Black Box warning about fatal
rashes, most serious warning
• Boxed warnings are special warnings
about a drug highlighted in the FDAapproved product information
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phenytoin (Dilantin)
• May be used to prevent seizures
• Promotes sodium outflow from cells,
stabilizing the neuronal membrane
• Be cautious of drug interactions
• IV phenytoin must be mixed carefully
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Side Effects of Phenytoin:
Dose Related
•
•
•
•
•
•
Ataxia
Diplopia
Dizziness
Drowsiness
Encephalopathy
Involuntary movements
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Side Effects of Phenytoin:
Non-Dose-Related
• Gingival hyperplasia
• Peripheral neuropathy (pain in
extremities
• Vitamin deficiencies
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pregabalin (Lyrica)
• Reduces release of neurotransmitters
glutamate, norepinephrine, substance P
• Similar to gabapentin, more potent. Fewer
side effects than other anticonvulsants
• Controlled substance, Schedule V
• Also approved to treat diabetic neuropathy
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taigabine (Gabitrol)
• Blocks reabsorption of GABA, allowing it to
bind to nerve cells which enhances normal
brain activity
• Should be taken with food
• Can cause seizures if patients who do not
have epilepsy use it off-label
• FDA has issued off-label use warning
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topiramate (Topamax)
• Thought to block sodium channels
which increases GABA activity and
decreases glutamine activity
• Causes significant cognitive effects
• Drink fluids to decrease risk of kidney
stones
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Discussion
Which neurotransmitters play the
greatest role in seizures?
The neurotransmitters are glutamate
(excitatory) and GABA (inhibitory).
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Terms to Remember
epilepsy
seizure
convulsion
partial seizure
generalized seizure
tonic-clonic seizure
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Terms to Remember
grand mal seizure
absence seizure
petit mal seizure
myoclonic seizure
atonic seizure
status epilepticus
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Terms to Remember
anticonvulsant
adjunct
ataxia
substance P
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Parkinson Disease
• Characterized by tremor when
resting, rigidity, and akinesia
(absence of movement)
• Poor posture control, shuffling gait,
loss of overall muscle control
• Usually affects people over 60
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Physiology of Parkinson
Disease
• Parkinson disease is result of alterations in
the extrapyramidal system
– Part of the CNS that controls motor activities
– Made up of the basal nuclei (basal ganglia)
• Most common extrapyramidal disease
• Parkinson has no definitive test, diagnosed
by symptoms
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Cutaway View of the Brain
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Physiology of Parkinson
Disease
• For normal muscle movement to be
performed, 2 main neurotransmitters
must be in balance
– Dopamine (inhibitor)
– Acetylcholine (stimulator)
• In Parkinson disease, these
neurotransmitters are not in balance
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Dopamine and Parkinson
Disease
• In the substania nigra, insufficient
dopamine is released to counteract
effects of Ach
• This causes excessive motor nerve
stimulation
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Substantia Nigra
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Parkinson Disease Drug
Therapy
• Improves functional ability and
clinical status of patients
• Aims at symptomatic relief, does not
alter disease process. No cure.
• Temporary or prolonged remission
• Side effects can be a problem
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Drug List
Anti-Parkinson Agents
– amantadine (Symmetrel)
– benztropine (Cogentin)
– bromocriptine (Parlodel)
– entacapone (Comtan)
– levodopa (Dopar)
– levodopa-carbidopa (Sinemet)
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Drug List
Anti-Parkinson Agents
– levodopa-carbidopa-entacapone
(Stalevo)
– pramipexole (Mirapex)
– rasagiline (Azilect)
– ropinirole (ReQuip)
– selegiline (Eldepryl)
– tolcapone (Tasmar)
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levodopa (Dopar)
• Metabolized to dopamine in brain, but
brain does not receive a full dose
• Very undesirable effects, including
nausea, vomiting, cardiac arrhythmia
• After about 5 years of therapy, 2/3 of
patients experience on-off
phenomenon
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levodopa-carbidopa
(Sinemet)
• Probably most common drug used in
Parkinson disease
• Carbidopa allows for lower doses of
levodopa to be used which decreases
side effects
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rasagiline (Azilect)
• Monoamine oxidase inhibitor (MAOI),
blocks breakdown of dopamine
• Initial therapy to improve symptoms
• Possible hypertensive crisis if patient
consumes foods with tyramine (aged
cheeses, cured meats, soy sauce)
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entacapone (Comtan)
• Second in class of anti-Parkinson
agents known as catechol-O-methyl
transferase (COMT) inhibitors
• Indicated for patients who have a
deteriorating response to levodopa
• Less toxic than tolcapone (Tasmar)
• Taken without regard to food
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Terms to Remember
Parkinson disease
basal nuclei
substantia nigra
on-off phenomenon
catechol-O-methyl transferase (COMT)
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Other Central Nervous
System Disorders
• Myasthenia gravis
• Attention-deficit hyperactivity disorder
and attention-deficit disorder
• Amyotrophic lateral sclerosis (ALS)
• Multiple sclerosis (MS)
• Alzheimer disease
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Myasthenia Gravis
• Autoimmune disorder of the
neuromuscular junction
• ACh receptors are destroyed at the
motor end plate
• Characterized by weakness and
fatigability, especially of skeletal
muscles
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Motor End Plate
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Presenting Signs
of Myasthenia Gravis
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•
•
•
•
•
Ptosis (drooping eyelid)
Diplopia (double vision)
Dyarthria (speech)
Dysphagia (swallowing)
Extremity weakness
Respiratory difficulty
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Treatment of Myasthenia
Gravis
• Acetylcholinesterase drugs can
produce improvements in all forms of
myasthenia gravis
• Drug therapy does not inhibit or
reverse the immunologic flaw
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Drug List
Agents for Myasthenia Gravis
– azathioprine (Imuran)
– cyclophosphamide (Cytoxan)
– edrophonium (Enlon, Reversol)
– neostigmine (Prostigmin)
– pyridostigmine (Mestinon)
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pyridostigmine (Mestinon)
• Blocks destruction of ACh
• Allows for ACh accumulation at the
synaptic junction
• Take with food or milk and at same
time each day
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cyclophosphamide (Cytoxan)
• Prevents cell division by targeting the
auto-immune portion of the disease
• Use chemotherapeutic precautions
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Attention-Deficit Disorders
• Attention-Deficit Hyperactivity
Disorder (ADHD)
• Attention-Deficit Disorder (ADD)
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Attention-Deficit Hyperactivity
Disorder (ADHD)
• Neurologic disorder characterized by
hyperactivity, impulsivity, and
distractability
• Symptoms can persist into adult life
• Most drugs used are amphetamines
and amphetamine derivatives, C-II
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Drug List
Attention-Deficit Disorders Agents
– atomoxetine (Strattera)
– dexmethylphenidate (Focalin), C-II
– dextroamphetamine-amphetamine
(Adderall), C-II
– lisdexamfetamine (Vyvanse)
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Drug List
Attention-Deficit Disorders Agents
– methylphenidate (Concerta, Daytrana
Metadate, Metadate ER, Methylin,
Ritalin, Ritalin-SR), C-II
– modafinil (Provigil, Sparlon)
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Dispensing Issues of AttentionDeficit Disorders Agents
Warning!
• ADHD drugs used for treatment as a group
must provide a medication guide to patient
or caretaker
• Technicians—check for mediation guide
when drug is handed to patient or
caretaker, even if drug is not C-II
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atomoxetine (Strattera)
• Nonstimulant indicated for treatment
of ADHD in patients 6 years and
older
• Controls impulsivity and activity
• Not a controlled substance, refills can
be called in
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methylphenidate (Concerta,
Daytrana Metadate, Metadate
ER, Methylin, Ritalin, Ritalin-SR)
• Drug of choice to treat attention-deficit
disorders
• CNS stimulant, C-II controlled substance
• Improved dosage allows the drug to be
taken only in the morning
• One form comes in a patch, improving
compliance
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methylphenidate (Concerta)
• Dosed once a day, in morning
• Outer layer dissolves to release part
of drug immediately
• Rest of drug is OROS tablet
– Slowly releases through pores in tablet,
leaving a ghost
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methylphenidate (Daytrana
Metadate)
• Patch form of methylphenidate
• Worn for 9 hours, then removed
• Drug is in the adhesive
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dextroamphetamineamphetamine (Adderall)
• C-II controlled substance
• Effects last about 6 hours
• Primary side effect is depression as
drug wears off
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Dispensing Issues of
Adderall
Warning!
• Look-alike and sound-alike
– Adderall (ADHD)
– Inderal (propranolol), beta blocker used
to treat anxiety
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Modafinil (Provigil, Sparlon)
• Sparlon is nonstimulant medication
• Indicated for treatment of ADHD in
patients 6 years and older
• Increases mental alterness
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Amyotrophic Lateral
Sclerosis (ALS)
• Also known as Lou Gehrig disease
• Progressive degenerative disease of
the nerves
• Muscle weakness, paralysis, and
eventually death
• Cause: excessive levels of glutamate
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Drug List
Agent for Amyotrophic Lateral
Sclerosis
– riluzole (Rilutek)
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riluzole (Rilutek)
• First drug approved for amyotrophic
lateral sclerosis
• Inhibits release of glutamate
• Seems to improve survival rate by
3 months in some patients
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Multiple Sclerosis (MS)
• Autoimmune disease in which myelin
sheaths around nerves degenerate
• Patient loses use of muscles, and
often eyesight is affected
• Some drugs can slow progression
• No cure
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Drug List
Multiple Sclerosis Agents
– baclofen (Lioresal)
– glatiramer acetate (Copaxone)
– interferon beta-1a (Avonex, Rebif)
– interferon beta-1b (Betaseron)
– mitoxantrone (Novantrone)
– tizanidine (Zanaflex)
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glatiramer acetate
(Copaxone)
• Seems to block the autoimmune reaction
against myelin that leads to nerve damage
• Decreases frequency of relapses
• Not been shown to slow disease progress
• Given everyday by subcutaneous injection
• Must be frozen
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tizanidine (Zanaflex)
• Indicated to reduce muscle spasticity
in MS and spinal cord injuries
• Oral drug
• Side effects: dry mouth, sedation,
dizziness, and hypotension
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Alzheimer Disease
• Progressive form of dementia
• Changes personality and behavior
• No treatments can cure or reverse
• Drugs can slow the disease
• Depression often treated with
antidepressants according to symptoms
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Progression of Alzheimer
Disease
1. Memory deficit, forgetfulness,
misplacements of ordinary items
2. Inability to complete complex tasks
3. Complete incapacitation,
disorientation, and failure to thrive
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Drug List
Agents for Alzheimer Disease
– donepezil (Aricept)
– galantamine (Razadyne)
– ginkgo (many)
– memantine (Namenda)
– rivastigmine (Exelon)
– tacrine (Cognex)
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tacrine (Cognex)
• Cholinesterase inhibitor
• Most common side effect: increase in
liver lab values
• Taken 4x a day on an empty stomach
• Side effects: nausea, vomiting
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donepezil (Aricept)
•
•
•
•
Convenient to use
Few side effects
Improves memory and alertness
Give once a day at bedtime
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Dispensing Issue of Aricept
Warning!
• Look-alike and sound-alike
– Aricept
– Aciphex (rabeprazole), GERD
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memantine (Namenda)
• May have fewer side effects and
better tolerated than other drugs
• Evidence that this drug slows
advancement of Alzheimer disease
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Terms to Remember
myasthenia gravis
motor end plate
ptosis
diplopia
dysarthia
attention-deficit hyperactivity
disorder (ADHD)
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Terms to Remember
amyotrophic lateral sclerosis (ALS)
Lou Gehrig disease
multiple sclerosis (MS)
Alzheimer disease
gingko
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Assignments
• Complete Chapter Review activities
• Answer questions in Study Notes
document
• Study Partner
– Quiz in review mode
– Matching activities
– Drug tables
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