Seizures
1
What is a Seizure?
2
What is a seizure?
I. Caused by uncontrolled, chaotic electrical activity in the brain.
II. This produces sensory, cognitive or muscular activity.
Muscular activity is in the form of:
a. Tonus (muscle contraction)
b. Clonus (alternate contraction and relaxation)
c. A complete relaxation/paralysis.
- lose all muscle tone and fall down
3
Provoked vs. Unprovoked
Seizures
4
Provoked vs. Unprovoked Seizures
• Unprovoked seizures are also referred to as primary or
idiopathic seizures
– There is no identifiable cause
• Provoked seizures have an identifiable cause
– Injury to the CNS
– Metabolic syndrome
• Ex. acidosis
– Fever
• Especially common in children
– Treating the cause of the seizure may help alleviate the
symptoms
5
Seizures
6
Seizures
•
I. We think of seizures as starting in some focus (small area) of irritable brain
tissue where the excitatory influences greatly exceed the inhibitory influences.
- The neurons in that area are firing and developing action potentials willingly
•
II. The focus generates chaotic electrical activity that spreads across the brain
- If it spreads throughout the whole brain, this is a generalized seizure.
- If it spreads through part of the brain, this is a partial seizure.
•
III. Surgery to relieve seizures (which is done only in cases that cannot be treated
with drugs) either
- Excises the irritable focus that is generating the seizure
- Cuts the tracts that provide an avenue for spread of the chaotic electrical activity.
•
IV. Deep brain stimulation may also be useful.
7
Classification of Seizures
8
Classification of Seizures
• Partial seizures
• Generalized seizures
9
Classification of Seizures
Partial Seizures
10
Classification of Seizures
Partial Seizures
• Simple partial seizures - no impairment of consciousness
• No falling down, aware of surroundings, may do odd
physical movements, such as smacking lips
• Complex partial seizures - impairment of consciousness
• Partial seizures may evolve to secondarily generalized
seizures.
11
Classification of Seizures
Generalized Seizures
12
Classification of Seizures
Generalized Seizures
• Absence seizures (typical or atypical) - involve loss of consciousness for a
brief time of 10-30 seconds.
• Although there is a loss of consciousness, the person does not fall
down
• Atonic seizures - involve sudden loss of muscle tone
• More common in children
• Can be associated with injury
• Myotonic seizures - sudden muscle contractions that last for 1 second
• Clonic seizures - Rapidly repeated flexor motions
• Tonic seizures - muscle contraction and rigidity
• Tonic-clonic seizures - initial muscle contraction followed by repeated
flexor motions
• Status epilepticus – a seizure of any type that continues for many minutes
or returns after a brief pause.
13
The Best Definition for a Seizure
that Involves the Entire Brain is
Which of the Following?
14
The Best Definition for a Seizure that Involves the
Entire Brain is Which of the Following?
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1. A partial seizure
2. An atonic seizure
3. A generalized
seizure
4. A tonic-clonic
seizure.
Microglioma
16
McCance & Heuther, Pathophysiology: The Biologic Basis for Disease in Adults & Children, 4th ed., 2002, Mosby, p.450.
•Partial seizure activity on an EEG of a patient with a brain tumor (a
microglioma)
•The seizure is only occurring where the leads five and six are located,17in
the parietal lobe
Antiepileptic Drugs (AEDs):
Mechanism of Action
18
Antiepileptic Drugs (AEDs): Mechanism of Action
All AEDs prevent the spread of aberrant electrical activity by raising
the threshold of the neuron so that action potentials do not
occur as readily or as often
I.
AEDs alter (block) sodium channels on the neuronal cell membrane by raising the threshold at
which neuronal cells depolarize to produce action potentials. This limits the spread of seizure
activity. To illustrate:
Threshold Potential with AED’s
Threshold Potential-no AED
Resting Potential
II. AEDs block Ca+2 channels on neuronal cell membrane. For some neurons, this produces the same
effect as blocking Na+ channels , that is, limiting the spread of seizure activity.
19
Antiepileptic Drugs (AEDs): Mechanism of
Action
III. AEDs enhance the activity or concentration of GABA (an
inhibitory neurotransmitter) in order to restore the
balance between excitatory and inhibitory
neurotransmitters rather than having an excess of
excitatory neurotransmitters. This raises the threshold
and makes it less likely that an individual neuron will
fire, thus limiting the spread of seizure activity.
IV. Only about 60-70% of epileptic patients can have their
seizures completely controlled with drugs.
20
GABAergic Neurotransmission
21
GABAergic Neurotransmission
GABA = gamma aminobutyric acid
•Widely distributed in brain
•Major source of synaptic inhibition in CNS
•Binds to ____ receptors?
Effects of GABA on its receptor:
•Inhibition of neurotransmission
•Clinical decrease in anxiety level
•Decreased seizure activity
22
Clinical Choice of AEDs
23
Clinical Choice of AEDs
• Choice of AED depends on:
– Type of seizures
– Patient-related variables, such as age and
health status.
• Monotherapy is the desired goal, although
combination therapy may be necessary.
24
Types of Anti-Epileptic Drugs
25
Seizure Type
Partial
Simple partial, complex partial, and
secondarily generalized
Drugs Used for Treatment
Traditional AEDs
Newer AEDs
Carbamazepine
Phenytoin
Valproic acid
Phenobarbital
Primidone
Oxycarbazepine
Gabapentin
Lamotrigine
Levetiracetam
Pregabalin
Lacosamide
Tonic-clonic
Carbamazepine
Phenytoin
Valproic acid
Phenobarbital
Primidone
Lamotrigine
Topiramate
Absence
Ethosuximide
Valproic acid
Lamotrigine
Myoclonic
Valproic acid
Topiramate
Primary generalized
Lehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier, p. 216
26
Monitoring Plasma Levels of
AEDs
27
Monitoring Plasma Levels of AEDs
I. For most seizure disorders and most AEDs, plasma levels are
monitored so that dosages can be adjusted to keep them within
the therapeutic range.
A.
Many AEDs have narrow therapeutic windows with toxic
effects occurring with small variations in dosage.
B. Many AEDs have complicated metabolism (pharmacokinetics)
such that different patients at different times may have widely
different rates of elimination of the drug.
C. There are many interactions between AEDs and other drugs,
some of which may slow down or speed up metabolism of the
AED.
D. Most treatment failures are due to a decline in drug levels
below the therapeutic range – either because the patient is
not taking the drug as directed or because something has
happened to speed up metabolism of the drug.
28
Which Drug can be Used for All
Types of Seizures?
29
Which Drug can be Used for All Types of
Seizures?
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Phenytoin
Diazepam
Ethosuximide
Valproate
Ph
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2.
3.
4.
25% 25% 25% 25%
Phenytoin (Dilantin)
Introduction
31
Phenytoin (Dilantin)
Introduction
Uses
Partial seizures and generalized tonic-clonic
- Used for a variety of seizure types (except absence)
Administration
PO: Absorption varies, but now different brands/manufacturers are standardized.
Chewable tablets are not interchangeable with capsules.
IV: →cardiovascular collapse if administered too rapidly
fosphenytoin (phenytoin prodrug) IV is much easier to administer.
- much easier to administer IV
Pregnancy
C – associated with increased incidence of birth defects and growth retardation.
- Most anti-seizure drugs are pregnancy category C or D
Distribution:
85-95% protein bound – since drug levels are very important, free levels are usually
obtained.
High lipid solubility, much like most drugs that can cross the blood-brain barrier
Other Information
Very old anti-seizure drug
Quite effective
Difficult to give IV
- Must give it slowly or else it will cause heart problems
32
Phenytoin (Dilantin)
Pharmacokinetics
33
Phenytoin (Dilantin)
Pharmacokinetics
Metabolism/
excretion
t ½: dose-dependent – higher doses→longer t ½;
Narrow therapeutic range (drug levels MUST be
obtained).
Metabolized by the liver
Eliminated by P450/ bile, feces
Multiple drug interactions at the level of P450 enzymes.
Induces P450 enzymes (increases its own rate of
metabolism and that of other drugs metabolized by the
same enzyme).
As the person takes the drug, they become better able
to eliminate the drug because of induction of P450 34
so
the dose must increase
Fosphenytoin (Cerebryx®)
35
Fosphenytoin (Cerebryx®)
•Phenytoin is administered IV in a vehicle of pH~13.
•It precipitates readily in standard IV fluids.
•Too rapid administration (>50 mg/min) can cause
serious cardiac arrhythmias or cardiovascular collapse.
•How to fix this problem?
•Give a prodrug of phenytoin (fosphenytoin) which is
soluble in standard IV solutions and can be given more
rapidly (150 mg/min).
•Fosphenytoin is metabolized to phenytoin by enzymes in
the RBCs – it is converted to phenytoin very quickly. 36
CAUTION:
Name-Alikes
37
CAUTION:
Name-Alikes
• (Celexa®) citalopram = antidepressant
• (Celebrex®) celecoxib = Cox-2 NSAID
• (Cerebryx®) fosphenytoin = anticonvulsant
38
Phenytoin
Nonlinear Pharmacokinetics
39
Phenytoin
Nonlinear Pharmacokinetics
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 225.
•For most drugs, as the dose increases, the blood level increases
•For phenytoin, small increases in dosage can lead to big increases in
blood levels because as blood levels increase, metabolism slows
40
down (because the half-life is dose dependent).
Question
A Scenario with Phenytoin
Your patient is a newly diagnosed epileptic. Three weeks
ago, he was started on phenytoin. Free drug levels
obtained after a week were in the therapeutic range. He
has continued with the same dose since then. He was
seizure-free until yesterday, when he had a generalized,
tonic-clonic seizure. Drug levels measured after his
seizure were sub-therapeutic.
What happened?
41
What Happened?
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2.
The patient is not taking his
medicine.
The patient’s cytochrome P450
enzymes increased (were
induced), so he is metabolizing
the drug faster and levels
declined.
The first lab tests were in error.
The patient’s seizures have
become refractory to
phenytoin.
Th
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Phenytoin
Adverse Effects: Neurotoxicity
43
Phenytoin
Adverse Effects: Neurotoxicity
Adverse Effects
Nursing/Pt Teaching
•Therapeutic range: 10-20
mcg/ml for patients with
normal serum albumin and
no competing drugs.
•Seizure diary
•Monitor levels
•Emphasize need for periodic
blood tests and whenever dose
changed!!!
•Toxic levels:
•Teach to space meds and take as
>20 mcg/ml→nystagmus
ordered
>30-40 mcg/ml → ataxia/ gross •Do not switch between chewable
motor changes (may be
tablets and capsules.
permanent)
>50 mcg/ml→coma
44
Phenytoin
Adverse Effects: Skin
45
Phenytoin Adverse Effects: Skin
Rash—risk of severe reaction •Assess skin
Ex. Stevens-Johnson syndrome •Teach to report any rash
Stevens-Johnson Syndrome (a.k.a. toxic epidermal necrolysis or
erythema multiforma), which can (rarely) be fatal.
See carbamazepine-induced SJS under “Interesting
Articles” on Blackboard
http://www.sjsupport.org/
46
Phenytoin
Other Adverse Effects
47
Phenytoin: Other Adverse Effects
THREATENING
•Brush teeth bid-soft
brush, floss qd
•Emphasize need for
dental care
Decreased effects of folic acid,
Ca+2, vitamin K, and  vitamin D
absorption
•Patient assessment
•Emphasize need to
take supplements
Gingival hyperplasia—the gums
overgrow; gross but NOT LIFE-
48
Carbamazepine (Tegretol®
Carbatrol® and others)
49
Carbamazepine (Tegretol®, Carbatrol® and Others)
Uses
Seizure disorder (partial and tonic-clonic seizures), trigeminal neuralgia, bipolar
disorder, neuropathic pain.
Absorption
Delayed and variable (bioavailability ~80%), PO only.
Pregnancy
Category D
Distribution:
Lipid soluble
Metabolism/
excretion
Hepatic metabolism (avoid grapefruit juice and other inhibitors)
P450 inducer – increases its own metabolism and that of other drugs metabolized
by the same enzymes.
Adverse Effects and
Nursing notes/teaching
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Bone marrow suppression/aplastic anemia – immunocompromised
Rash (possibility Stevens-Johnsons syndrome)
Photosensitivity.
Monitor levels, CBC (complete blood count)
Neurologic SE will decrease with time.
Not as sedating as phenytonin, which is a benefit
Older drug that is less expensive because it is off patent
Can result in ataxia and motor problems
50
Oxcarbazepine
51
Oxcarbazepine
• As effective as carbamazepine but better
tolerated
– Does not cause bone marrow suppression
• Otherwise, adverse effects are similar to
carbamazepine
52
Which of the Following possible
Adverse effects is NOT Shared
between Phenytoin and
Carbamazepine?
53
Which of the Following possible Adverse effects is
NOT Shared between Phenytoin and Carbamazepine?
1. Stevens-Johnson
syndrome
2. Ataxia/neurologic
effects.
3. Aplastic anemia
4. Mild sedation
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Valproic Acid (Depakine® and
others)
55
Valproic Acid (Depakine® and others)
Uses
All seizure types (the only one!) Bipolar disorder, migraine prophylaxis.
Absorption
Well absorbed. PO only.
No IV preparation
Pregnancy
Category D (Recent data indicates that valproate is more teratogenic than other
antiepileptics)
Distribution:
Lipid soluble
Metabolism/
excretion
Hepatic metabolism.
Adverse Effects and
Nursing notes
Rare severe hepatotoxicity.
Nausea and vomiting (use enteric coated prep)
Rare severe pancreatitis
Rash
Weight gain
Hair loss
Tremor
Blood dyscrasias.
56
Phenobarbital and Primidone
(Mysoline®)
57
Phenobarbital and Primidone (Mysoline®)
Uses
Partial and generalized tonic-clonic seizures.
Primidone is a prodrug for phenobarbital
Absorption
PO; IV in an emergency
Pregnancy
D
Distribution:
High lipid solubility
Metabolism/
excretion
t ½: 50-140h (adult) 35-75h (child);
MAJOR P450 INDUCER – increases its own
metabolism and that of other drugs
Adverse
Effects and
Nursing Notes
•Generalized CNS depressant and sedative/hypnotic
•Paradoxical agitation in children/elderly
•Have generally been replaced by newer AEDs that cause
less CNS depression
•Can cause folic acid and Vitamin K depletion like
phenytoin.
58
Ethosuximide (Zarontin®)
59
Ethosuximide (Zarontin®)
Uses
*Absence seizures only.
Absorption
PO only. Well absorbed.
Pregnancy
C
Distribution:
Lipid soluble
Metabolism/
excretion
Hepatic and renal; long t1/2
*Does not induce hepatic enzymes (but might be affected
by concurrent administration of a drug that does induce).
Adverse
Effects and
Nursing notes
•Rare systemic lupus erythematosus, aplastic anemia.
- can be reversed if stopped early enough
•Mostly side effects are mild neurological effects such as
dizziness, lethargy, that disappear with use.
•Nausea Vomiting – give with food.
60
AEDs and Pregnancy
61
AEDs and Pregnancy
•Uncontrolled seizures in the mother are bad for the fetus.
•BUT, nearly all of the AEDs are associated with an
increased risk of birth defects and growth retardation.
•Most are pregnancy category D.
•Drug levels should be monitored during pregnancy so as
to use the least possible drug.
•BUT, because of a pregnant woman’s increased blood
volume (which would produce lower drug levels) and
increased renal perfusion (which increases the rate of
elimination), doses may have to be increased to
62
maintain therapeutic levels of drug.
Effects of AEDs during Pregnancy
63
Effects of AEDs during Pregnancy
•Phenytoin and other AEDs alter folate metabolism, so it is
recommended that pregnant women on these drugs take 2
mg (RDA, 400 mcg) of folate per day.
•Need folate in order to prevent neural tube defects
•Phenobarbital, phenytoin, carbamazepine, and primidone
reduce levels of clotting factors by inducing hepatic
enzymes. Pregnant women on these drugs should increase
their intake of Vitamin K and infants should be given IM
Vitamin K after delivery.
64
Oral Contraceptives (OCPs)
65
Oral Contraceptives (OCPs)
•The AEDs that induce hepatic enzymes will
speed the elimination of OCPs, possibly
rendering them ineffective!
•Women on both AEDs and OCPs may need a
higher dose OCP for effective contraception.
66
Discontinuing AEDs
67
Discontinuing AEDs
•Patients who have been seizure-free for many years
might want to discontinue their AED to see if they
really need it.
•AEDs should always be discontinued by gradually
reducing the dose.
•If the patient is on more than one AED, one should
be tapered and discontinued before beginning to taper
and discontinue the other.
68
Compliance
69
Compliance
•Patients must be careful to take their AEDs on
time and not miss a dose.
•If blood levels fall low enough, a seizure may
occur.
•The patient with epilepsy faces a possibly lifelong need for the drug.
•Compliance is a major issue.
70
AED’s
Additional Patient Teaching
71
AED’s
Additional Patient Teaching
• Meds control seizures but do not correct cause.
• Instruct patients in the importance of wearing medic
alert bracelet stating they have epilepsy.
• State laws about driving apply.
• Teach patients to avoid sudden cessation of AED.
• Teach safety precautions relevant to CNS depression.
– Need to be careful about doing anything active or with
dangerous materials
• Teach patients to avoid simultaneous use of other
CNS depressants (Ex. ETOH).
• Shake suspension well before each use.
72
Medical Emergency
Status Epilepticus
73
Medical Emergency
Status Epilepticus
• Definition: Rapid succession of any
type of epileptic seizures.
• Sudden withdrawal of anti-seizure
medications may precipitate seizures
or status epilepticus.
• Although status epilepticus can
involve any seizure type, tonic-clonic
status epilepticus is the most
dangerous because of its effect on
respiration.
– They are not taking in air because they
are not breathing due to the involvement
of the respiratory muscles in the seizure
74
Tonic-Clonic Status Epilepticus
•The patient may need to be intubated and ventilated since
respiratory muscles are involved with this seizure type.
•IV access must be established so drugs can be given.
•Although diazepam (valum) or lorazepam (atavan) may stop the
seizure, the patient must receive a loading dose of a long-acting
anticonvulsant such as fosphenytoin to prevent the seizure from
returning.
•Lactic acidosis and hyperthermia due to extreme muscle activity
may be complications from a prolonged seizure.
•Patient is in anaerobic metabolism because they are not
breathing, which produces lactic acid
75
•Hyperthermia can lead to brain damage
Benzodiazepines (BZ’s)
76
Benzodiazepines (BZ’s)
Lorazepam (Ativan®)
Diazepam (Valium®)
Uses
Tonic-clonic status epilepticus (give IV)
Both are Schedule IV controlled substances
Pregnancy
D
D
Metabolism/
excretion
Has a longer effect than
diazepam, up to 72 hours
Anti-seizure effect is short-lived
Repeat dose (~5 mg for an adult) q
10-15 min up to 30mg if seizures
are continuing, then q2-4 prn
Notes
•Long-acting AED must be given during/after BZ administration
due to short term effects of BZ.
•Emergency resuscitation equipment must be available
•Do not mix with other meds in the same IV line – will
precipitate!
77
Disorders of Motor Function
78
Coordinated Movement
79
Coordinated Movement
• Produced by coordinated contractions/relaxations of the particular
muscles that affect a particular joint. These are controlled in the
CNS by the motor pathways in the cortex, midbrain, and cerebellum
that work together to produce smooth, coordinated movement.
• The following terminology should be reviewed from A & P:
• Extensors
– Muscles that increase the angle of a joint
• Flexors
– Muscles that decrease the angle of a joint
• Agonists
– Muscles that enable a given movement
• Antagonists
– Muscles acting to oppose a given agonist muscle
• Synergists
– Muscles that work together to stabilize a joint or cause a 80given
movement.
Disorders of Motor Function
81
Disorders of Motor Function
• Upper motoneuron lesions
– ALS
– Multiple Sclerosis
– Parkinson’s Disease
• Lower motoneuron lesions
– Progressive muscular atrophy
• Neuromuscular Junction (NMJ) Problem
– Myasthenia gravis
• Myopathy (muscle cells)
– Muscular (Disuse) Atrophy
– Muscular dystrophy
– Polymyositis
– Rhabdomyolysis
– Malignant hyperthermia
82
Porth, Pathophysiology, Concepts of Altered Health
States, 7th ed., 2005, Lippincott, p. 1195.
Disorders of Motor Function
Upper Motoneuron Lesions
83
Disorders of Motor Function
Upper Motoneuron Lesions
• Can involve the motor cortex, through the internal
capsule, other brain structures, or spinal cord,
through which the corticospinal or corticobulbar
tracts descend.
• Cause a spastic paralysis.
84
Disorders of Motor Function
Lower Motoneuron Lesions
85
Disorders of Motor Function
Lower Motoneuron Lesions
• Disrupt communication between spinal cord and
muscle
• Causes a flaccid paralysis.
86
Disorders of Motor Function
Neuromuscular Junction
Problems
87
Disorders of Motor Function
Neuromuscular Junction Problems
• The NMJ is the synapse between the lower motor
neuron and the muscle
• NMJ disease that prevents communication between
nerve terminal and muscle.
88
Disorders of Motor Function
Myopathy
89
Disorders of Motor Function
Myopathy
• Disease of the muscle that makes it unable to
respond to the nerve impulse.
90
Myopathy
Disorders of Skeletal Muscle
91
Myopathy
Disorders of Skeletal Muscle
• Muscular (Disuse) Atrophy
– If a normally innervated muscle is not used for long periods, the muscle cells
shrink in diameter, lose much of their contractile protein, and weaken.
• Muscular dystrophy
– A group of genetic disorders that produce progressive deterioration of skeletal
muscles because of mixed muscle cell hypertrophy, atrophy, and necrosis.
• Other myopathies
–
–
–
Polymyositis
Rhabdomyolysis
Malignant hyperthermia
92
Disorder of the NMJ
Myasthenia Gravis
93
Disorder of the NMJ
Myasthenia Gravis
• The patient has antibodies
that attack the nicotinic
skeletal muscle
acetylcholine receptors.
• These receptors are
destroyed, making it
hard/impossible for the
muscle to respond to nerve
impulses.
• Treated with
immunosuppressive
therapy and
acetylcholinesterase
inhibitors (covered later).
Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 797.
94
Upper Motor Neuron Diseases
95
Upper Motor Neuron Diseases
I. Amyotropic lateral sclerosis (ALS or Lou
Gehrig’s disease). Also has lower motor neuron
effects – the result is a spastic paralysis.
II. Multiple sclerosis
III. Parkinson’s disease and other
extrapyramidal problems.
96
Amyotrophic Lateral Sclerosis
(ALS)
97
Amyotrophic Lateral Sclerosis (ALS)
•
•
•
•
•
•
•
A devastating disease in which there is death
of motor neurons in the cortex, ventral horn
of the spinal cord, and motor nuclei in the
brain stem.
The disease typically follows a progressive
course, with a mean survival period of 2 to 5
years from the onset of symptoms.
No effective treatment exists.
Sensory function, intellect, and movement of
eyes are preserved.
Death occurs from respiratory failure.
Prolonged survival with a respirator (Stephen
Hawking) is possible but requires extreme
support measures.
The person’s sensation and intellect, as well as
eye movement, are preserved
•
Can be in an uncomfortable position but cannot
do anything to change it
(See ALS case study under “Interesting Articles” on
Blackboard.)
Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 1195.
98
Multiple Sclerosis (MS)
99
Multiple Sclerosis (MS)
A. A demyelinating disease of the CNS. It affects all myelinated neurons in the CNS.
B. Most common non-traumatic cause of neurologic disability among young and
middle-aged adults.
- More common in women
C. Probably an autoimmune disorder.
D. Characterized by exacerbations and remissions over many years in several
different sites in the CNS.
1. Initially, there is normal or near-normal neurologic function between
exacerbations.
2. As the disease progresses, there is less improvement between exacerbations
and increasing neurologic dysfunction.
100
Multiple Sclerosis (MS)
E. Initial symptoms frequently involve the eyes – double vision,
blurred vision, etc.
-
Because the muscles in the eyes are highly active and thus
are affected sooner than other muscles
F. As the disease progresses, additional symptoms of paralysis and
sensory dysfunction (numbness, tingling, etc.) appear.
G. Finally over a period of years, the person may become bedridden and die.
H. Treatment is by immunosuppression, which has had varying
success.
101
Basal Ganglia/Extrapyramidal
System
102
Basal Ganglia/
Extrapyramidal System
• A group of deep, interrelated
subcortical nuclei (red nucleus,
substantia nigra) that play an
essential role in control of
movement.
• They receive indirect input from
the cerebellum and from all
sensory systems, including vision,
and direct input from the motor
cortex.
– They function in the
organization of inherited and
highly learned and automatic
movement programs.
– They also are involved in
cognitive and perception
functions.
103
McCance & Heuther, Pathophysiology: The Biologic Basis for Disease in
Adults & Children, 4th ed., 2002, Mosby, p.373.
Characteristics of Disorders of
the Basal Ganglia
104
Characteristics of Disorders of the Basal
Ganglia
• Involuntary movements
• Alterations in muscle tone
– Either too much or too little muscle
tone
• Disturbances in body posture
105
Types of Involuntary Movements
106
Types of Involuntary Movements
• Tremor: rhythmic shaking of an extremity or the head – resting or
intention.
• Tics: irregularly occurring coordinated movements, such as
winking, grimacing, shrugging, or even speech.
• Chorea: Brief, rapid, coordinated, graceful movements.
• Athetosis: Slow, continuous, wormlike movement, frequently
associated with spasticity.
• Ballismus: Violent, sweeping movements.
• Dystonia: Grotesque and twisted postures due to twisting and
turning motions.
• Dyskinesias: Rhythmic, repetitive bizarre movements, chiefly of
107
the face.
Parkinson’s Disease (PD)
108
Parkinson’s Disease (PD)
• Definition
– A degenerative disorder
of basal ganglia function
that results in variable
combinations of tremor,
rigidity, and bradykinesia
(slowed movement)
• Cause
– Progressive destruction of
the nigrostriatal pathway
•
Results in subsequent
reduction in striatal
concentrations of
dopamine.
• Clinical Syndrome
– Parkinsonism
Porth, 2007, Essential of Pathophysiology,
2nd ed., Lippincott, p. 807
109
Characteristics of Parkinson’s
Disease (PD)
110
Characteristics of Parkinson’s
Disease (PD)
Tremor - a resting tremor that is embarrassing for patients but
doesn’t impair their function very much because it is resting.
- when the patient is at rest, there is a tremor
- when the patient is moving, there is not a tremor
Rigidity - a debilitating symptom in which the patient will
sometimes “freeze” and be unable to move.
- it can require the person to take a few seconds or minutes
to move
Bradykinesia - the main difficulty is initiating movement and once
the movement is started it is sometimes difficult to stop.
111
End-Stage Parkinson’s Disease
112
End-Stage Parkinson’s Disease
•Although movement problems predominate in
early to mid-stage PD, cognitive defects can
appear in late-stage disease.
•End-stage
•The patient is bedridden, unable to move at all,
and may be unresponsive.
113
Parkinson’s Disease
Therapeutic Goals
114
Parkinson’s Disease
Therapeutic Goals
• PD is caused by a deficient of dopamine in the
striatum
• Normally, dopamine and Ach balance each other
out
– In PD, the amount of dopamine is too little
• Treatment
– Increase dopamine
– Decrease acetylcholine
115
Parkinson’s Disease and Therapeutic Goals
116
Dopaminergic and Cholinergic
Pathways and Effects
117
Dopaminergic and Cholinergic Pathways and Effects
Dopamine (DA)
pathways and effects
•Mesocortical: DA
affects cognition
Acetylcholine (ACh) pathways and
effects
•Cortex and Limbic System: ACh
affects learning and memory, as
well as wakefulness and attention
•Mesolimbic: DA
•Striatum – ACh is excitatory to
affects emotions
GABA neurons which modulate
•Striatum: DA is
movement.
inhibitory to GABA
•Peripheral Nervous System (PNS):
neurons which modulate (Useful throughout the body):
movement
Regulation of autonomic nervous
•Dopamine is important system and at PNS end organs.
in psychosis – there is
Excitatory transmission at the NMJ
118
usually too much
Nigrostriatal Pathways
119
Nigrostriatal Pathways
- Neurons that
originate in the
substantia nigra send
their axons into the
striatum
LeWitt P. N Engl J Med 2008;359:2468-2476
Dopamine in PD
121
Dopamine in PD
• DA is normally synthesized in neurons that originate in
the substantia nigra, a pigmented region of the brainstem,
and send their axons to the striatum, a component of the
extrapyramidal motor system.
• Progressive death of the nigrostriatal neurons is
responsible for PD.
• After being released into a synapse, dopamine can be
taken up by dopamine reuptake pumps on presynaptic
neurons, or degraded by COMT (catecholamine-O-methyl
transferase) or by MAO (monoamine oxidase).
122
Abnormal Neurotransmission in
Parkinson’s Disease
123
Abnormal Neurotransmission in PD
124
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 183.
Dopamine Synapse
125
Dopamine Synapse
•In a dopaminergic
neuron, the
neurotransmitter (T) is
dopamine.
•Postsynaptic
receptors are
dopaminergic.
•Neurotransmitter is
removed from the
synapse by reuptake (5a)
or metabolism by COMT
or by MAO (5b).
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 101.
126
Anti-Parkinson Drugs
127
Anti-Parkinson Drugs
Class
Activity
Drugs
Dopamine replacement
 dopamine in the synapse
levodopa/carbidopa
COMT inhibitors
entacapone and others
MAO inhibitors
selegiline
Dopamine agonists
- Binds to dopamine
receptors and activates
them
 Stimulation of dopamine
receptors
bromocriptine and others
Anticholinergics
(antimuscarinics)
- Bind excess ACh
activity
Decrease stimulation of
muscarinic receptors
benztropine
diphenhydramine (Benadryl)
128
Levodopa/Carbidopa
129
Levodopa/Carbidopa
• Levodopa: Precursor to
dopamine that crosses the
blood-brain barrier by use
of the amino acid transport
– Cannot just give a person
dopamine because it is
charged and so cannot cross
the blood-brain barrier
• BUT—99% converted to
dopamine in periphery—
• SO—combined with
carbidopa, which is an
inhibitor of the enzymes
that convert L-dopa in the
periphery
– Decreases peripheral
conversion so that more
levodopa reaches the brain.
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 186.
130
Levodopa/Carbidopa
Practical Use
131
Levodopa/Carbidopa
Practical Use
• Need to establish baseline assessment of
Parkinson signs prior to giving the drug
• Full effect may not be seen for weeks to months.
• May darken urine and/or sweat.
• Levodopa/carbidopa may ameliorate Parkinson
symptoms for a time, and then the dose might
have to be increased. This may continue for a
matter of years, but at some point the drug may
become ineffective, even at high doses.
132
Levodopa/Carbidopa
Diagram of the Effect of
Carbidopa
133
Levodopa/Carbidopa
Diagram of the Effect of Carbidopa
Lehne, 2009,
Pharmacology for Nursing
Care, 7th ed., Elsevier, p.
190.
134
Levodopa/Carbidopa
Pharmacokinetics
135
Levodopa/Carbidopa
Pharmacokinetics
Absorption
PO, empty stomach to prevent competition
with the dietary acids
High protein decreases absorption across the
gut and across the BBB
- should eat low protein foods
spaced during day
Distribution:
Transported across the gut and BBB by a
neutral amino acid transporter
Metabolism/
excretion
Degraded by COMT & MAO
Notes
Inhibits lactation
136
Levodopa
Adverse Reactions and Nursing
137
Levodopa
Adverse Reactions and Nursing
Adverse reaction
Nursing/pt teaching
•Abnormal movements occur
when there is too much dopamine
in the brain
- Choreiform
- Dystonic reactions
- Dyskinetic movements
- Involuntary movements
•Personality, behavioral, mental
health changes
- Depression
- Suicidal ideation
- Hallucinations
- Psychoses
•Patient assessment
•Need to report any signs
•Dosage of levodopa/carbidopa
may be decreased (but that might
cause more symptoms of PD)
•Patient assessment
•Need to report changes
•Advise about increased libido
•These effects occur because of
dopamine’s activity in other
138 areas
of the brain, not the striatum.
Levodopa
Adverse Reactions and Nursing
Adverse reaction
Nursing/pt teaching
•Hypertensive crisis if given
within 2-4 weeks of
monamine oxidase
inhibitors (MAOI)
Assess medication history
For concurrent administration of selegiline, titrate
dose carefully.
•Monitor BP, P, EKG
•Teach to change positions
slowly
•Orthostatic hypotension
•Cardiac dysrhythmias
139
Levodopa
On-Off Phenomenon
140
Levodopa
On-Off Phenomenon
•Most worrisome effect of Levodopa
•Acute loss of effect in previously effective regimen for levodopa/carbidopa – with
no relationship to the dosing interval.
•These symptoms may alternate with periods of choreiform movements.
• May be due to uneven supply of drug (sometimes too much, sometimes too little)
or other adaptive mechanisms in the brain.
• Low protein diet or giving the levodopa/carbidopa more frequently (maintain the
same daily dose) may help.
•See a You-Tube video in which Michael J. Fox is having choreiform movements.
•http://www.youtube.com/watch?v=ECkPVTZlfP8
141
Levodopa/Carbidopa
Wearing Off
142
Levodopa/Carbidopa
Wearing Off
• Loss of effect at the end of a dosing period.
• Due to low levels of drug.
• Increase the dose or decrease the dosing
interval.
143
Dopamine Agonists
144
Dopamine Agonists
•Dopamine agonists bind to the dopamine receptor and activate it
•Have no effect on dopamine levels, only on receptor activity
•Do not increase the level of dopamine as Levodopa does,
but change how the body reacts to it
•Pramipexole and ropinirole: non-ergot drugs selective for
dopamine receptors.
•Bromocriptine and pergolide: ergot derivatives also active at
serotonin and alpha receptors  SE.
•Side Effects: Nausea and vomiting, “sleep attacks” (rare).
•When dopamine agonists are used with levodopa, there is an
increased risk of orthostatic hypotension, hallucinations, and
145
dyskinesias.
Rotigotine (Neupro)
146
Rotigotine (Neupro)
• A transdermal dopamine agonist
• Approved in May, 2007
• Same side effects as the oral dopamine
agonists.
• Transdermal formulation may provide a
more constant blood level than oral dosing.
• Patients may like the convenience of oncedaily application.
147
COMT Inhibitors
148
COMT Inhibitors
•Used in conjunction with Levodopa and Carbidopa*
•Include entacapone and tolcapone (rare fatal liver damage).
•They prevent the peripheral degradation of levodopa (in addition
to the activity of carbidopa) and thereby increase the amount of
levodopa getting into the brain.
•COMT metabolizes some drugs
•COMT inhibitors will increase levels and activity of those
drugs
•Methyl dopa (a BP drug)
•Dobutamine (used in heart failure)
149
•Isoproterenol (a beta agonist).
Amantidine
150
Amantidine
•Falls under the category of dopamine releasers
•An antiviral drug used in the treatment of influenza.
•Effective in PD by increasing release of dopamine from the
presynaptic nerve terminal.
•Also is an antagonist at muscarinic receptors
•Symptoms include dry mouth, confusion, blurred vision, and
urinary retention.
•Helps by reducing the amount of ACh that can go to the
receptors, which restores a balance between dopamine and ACh
•Has a modest effect that wears off in 3-6 months
•Used as a second line drug for PD.
151
Anticholinergic Agents
152
Anticholinergic Agents
• Include
• Benztropine (Cogentin®)
• Trihexyphenidyl (Artane®)
• Diphenhydramine (Benadryl®)-antihistaminic with atropine-like effects
• Work by blocking the muscarinic receptors in the striatum
• Improves the functional imbalance between dopamine and ACh
• DO NOT USE IN patients WITH MEMORY LOSS, DEMENTIA OR
GLAUCOMA
• May exacerbate these problems
• Antimuscarinic side effects
• Ex. dry mouth, blurred vision, photophobia, urinary retention,
constipation, and tachycardia
• 2nd or 3rd line drugs for PD.
153
Deep Brain Stimulation for
Parkinson’s Disease
154
Deep Brain Stimulation for
Parkinson’s Disease
• A thin wire electrode is inserted into the brain through
a small hole in the skull and advanced into the
thalamus, globus pallidus, or subthalamic nuclei.
• The wire is connected to a neurostimulator that is
implanted under the skin in the chest area.
– The connecting wire is tunneled under the skin of the skull
and neck.
– The neurostimulator is programmed to send impulses to the
electrode which block the abberant impulses causing the
tremor or rigidity of PD.
• Used only for patients whose symptoms are not well
controlled with medication.
• DBS may also be useful for uncontrolled epilepsy.
Deep Brain Stimulation
http://www.daylife.com/photo/0fz6aHe0DY2ou
A PD patient is taking levodopa/carbidopa.
He experiences episodes of involuntary movements
of his head and neck midway between doses.
At other times, he has tremors and rigidity.
What is the problem?
157
A PD patient is taking levodopa/carbidopa. He experiences episodes
of involuntary movements of his head & neck midway between
doses. At other times, he has tremors & rigidity. What is the
problem?
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His dose of levodopa/carbidopa
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His dose of levodopa/carbidopa
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He has on/off phenomenon
He has wearing off
phenomenon.
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1.
Anesthetic and Neuromuscular
Blocking Agents
159
Types of Anesthesia
160
Anesthesia
General
Inhalation
Local
Parenteral
161
Balanced General Anesthesia
162
Balanced General Anesthesia
Results in:
• Loss of consciousness
• Analgesia
• Muscle relaxation
– Because it aids in surgical procedures if the
muscles are relaxed
163
The Process of General
Anesthesia
164
The Process of General Anesthesia
• Induction
• Maintenance
• Reversal
165
The Process of General
Anesthesia
Induction
166
The Process of General Anesthesia
Induction
• Induction: The patient is put under anesthesia very
quickly, so that he/she is unconscious in a matter of a
minute or so.
• During this time, the patient is often intubated
with the aid of a neuromuscular blocker that
paralyzes all skeletal muscles so that he or she can
be intubated quickly.
• Fast-acting IV drugs are usually used for induction.
167
The Process of General
Anesthesia
Maintenance
168
The Process of General Anesthesia
Maintenance
• Maintenance: The patient is maintained
under anesthesia, often with inhalation
agents.
• If intubated (which most people are),
neuromuscular blockade is maintained.
169
The Process of General
Anesthesia
Reversal
170
The Process of General Anesthesia
Reversal
• Reversal: The patient is brought to consciousness
very quickly by discontinuing the inhalation agent.
• Neuromuscular blockade is reversed and as soon
as spontaneous respirations and the gag reflex
return, the patient is extubated.
171
Intravenous Anesthetics
172
Intravenous Anesthetics
I. Short acting barbiturate: thiopental
- Used for induction
II. Benzodiazepines: diazepam (Valium®) or midazolam (Versed®)
- Used for sedation alone (“conscious sedation”) or as an
adjunct to other anesthetics, particularly for induction
III. Propofol (Diprivan®)
- Used as a continuous infusion for sedation and as an
induction agent.
IV. Ketamine:
- A dissociative anesthetic
- Has neuropsychiatric side effects.
173
Inhalation Anesthetics
Description
174
Inhalation Anesthetics
Description
•Want to know the minimum alveolar concentration that can produce
surgical anesthesia
•Surgical anesthesia – being able to be operated on without pain or
noticing it
•A mixture of inhalation anesthetics could be used.
•Combining halothane and nitrous oxide, for instance, cuts down
on the dose of each.
•Nitrous oxide does not produce good anesthesia by itself because we
can’t give 100% nitrous oxide
•Need to include some oxygen in the anesthetic mixture so the
person will not suffocate (don’t laugh, it’s happened).
175
Inhalation Anesthetics
Chart
176
Inhalation Anesthetics
Drug
MAC* (%)
Analgesic
Effect
Effect on
BP
105**
++++
none
Halothane
0.75
++

Desflurane
4.58
++

Enflurane
Isoflurane
1.68
1.15
++
++


Sevoflurane
1.71
++

Nitrous oxide
Adapted from Lehne, 2009, Pharmacology for
*Minimum alveolar concentration
Nursing Care, 7th ed., Elsevier, p. 253 177
**Surgical anesthesia cannot be attained with nitrous oxide alone.
Inhalation Anesthetics
Pharmacokinetics
178
Inhalation Anesthetics
Pharmacokinetics
Absorption
•Inhalation anesthetics are absorbed into the capillaries in the
lungs. Once in the bloodstream, they get into the brain where
they act to decrease neuronal activity.
Mechanism of Action
•Their mechanism of action is poorly understood but they
may increase the activity of GABA receptors somehow.
Elimination
•Most inhalation anesthetics are eliminated in the expired
breath.
179
Inhalation Anesthetics
Effects
180
Inhalation Anesthetics
Effects
• Nearly all inhalation anesthetics produce
decreased blood pressure
– Possibly because of their depression of the
nervous system
• Can be countered during surgery by administering
fluids or by using a vasopressor
181
Neuromuscular Blockers
182
Neuromuscular Blockers
• Used in many surgeries to produce complete muscle relaxation
(a.k.a. paralysis).
• The patient must be intubated and ventilated because the patient
cannot breathe.
• Two types of neuromuscular blockers
• A. Nondepolarizing.
• B. Depolarizing.
• Nondepolarizing agents can be reversed but a depolarizing agent
cannot be reversed.
183
What Types of Agents are Used
for Anesthesia Induction?
184
What Types of Agents are Used for
Anesthesia Induction?
1. Short-acting, intravenous
barbiturates or
benzodiazepines.
2. Anti-epileptic drugs
3. Inhalation anesthetics
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- Used in the maintenance part
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4. Reversal agents.
Local Anesthesia
186
Local Anesthesia
•Local anesthetics are sodium channel blockers – they prevent
transmission of pain impulses from the nociceptors to the spinal
cord.
•Local anesthetics are local because they are used topically – the
drug is delivered to the area where numbness is desired.
•Onset is fairly rapid but termination of activity is determined by
how fast the drug is absorbed into the bloodstream and disperses
from the site of action.
•Length of activity depends on how well the area is vacularized
•Ex. the gums are well vascularized
187
Local Anesthetics
Strategies to Prevent Diffusion
Away from the Site
188
Local Anesthetics
Strategies to Prevent Diffusion Away from the Site
•A vasoconstricting drug, such as epinephrine, is added to the local
anesthetic injection – this limits blood flow and prevents the
anesthetic from diffusing away. Normally, neither the local
anesthetic nor the vasoconstrictor has any systemic effect because
of the small amounts used at the site of local anesthesia.
•A tourniquet may be applied to a limb to keep the local anesthetic
confined to that limb.
•May be used if the person cannot undergo general anesthesia
for some reason
189
Local Anesthetics
Adverse and Allergic Reactions
190
Local Anesthetics
Adverse and Allergic Reactions
•Adverse reactions are uncommon because of
small doses used with topical application.
•However, allergic reactions can be serious – they
are rare but are more likely to occur with the ester
class of local anesthetics like procaine
(Novocaine) (esters are drugs formed by bonding
an alcohol with one or more organic acids)
•Allergic reactions can progress to anaphylaxis.191
Local Anesthetics
Use as a Nerve Blocker
192
Local Anesthetics
Use as a Nerve Blocker
•Local anesthetics can be used for nerve blocks to
produce regional anesthesia.
•The area around the nerve supplying a region is
infiltrated.
•Epidural anesthesia involves putting the local anesthetic
into the epidural space near where the nerve roots
supplying the area are exiting the spinal cord.
193
Local Anesthesia
Lidocaine
194
Local Anesthesia
Lidocaine
Drug
Lidocaine (an amide)
Class
Anesthetic; Local
Uses
Local, regional anesthesia
MOA
Blocks sodium channels which prevents nerve
impulse transmission
Administration
Local/regional
Onset
rapid
Duration
1-3 h
Special notes
•May be given with epinephrine to decrease blood
flow to the area and thereby prolong the anesthesia
•Wait for effects before doing procedure
•Swallowing precautions for oral use
195
•The most common local anesthetic
Things to Look Up or Ask
• Slide 22 – what receptor does GABA bind to?
• Slide 149 – COMT inhibitors should always be
used in conjunction with Levodopa and
Carbidopa, correct?
• Slide 151 - verify how decreasing ACh helps with
Parkinson’s Disease
• Slide 153 – what is the difference between
anticholinergic and antimuscarinic drugs
• Slide 163 – types of anesthesia in a mouth
procedure
196