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Seizures

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Title: Seizures


1
Seizures
1
2
What is a Seizure?
3
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
4
Provoked vs. Unprovoked Seizures
5
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

6
Seizures
7
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
8
Classification of Seizures
9
Classification of Seizures
  • Partial seizures
  • Generalized seizures

10
Classification of SeizuresPartial Seizures
11
Classification of SeizuresPartial 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.

12
Classification of SeizuresGeneralized Seizures
13
Classification of SeizuresGeneralized 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.

14
The Best Definition for a Seizure that Involves
the Entire Brain is Which of the Following?
15
The Best Definition for a Seizure that Involves
the Entire Brain is Which of the Following?
  1. A partial seizure
  2. An atonic seizure
  3. A generalized seizure
  4. A tonic-clonic seizure.

16
Microglioma
17
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, in the parietal lobe

17
18
Antiepileptic Drugs (AEDs) Mechanism of Action
19
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 AEDs
Threshold Potential-no AED
Resting Potential
II. AEDs block Ca2 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
20
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
21
GABAergic Neurotransmission
22
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
23
Clinical Choice of AEDs
24
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
25
Types of Anti-Epileptic Drugs
26
Seizure Type Drugs Used for Treatment Drugs Used for Treatment
Seizure Type Traditional AEDs Newer AEDs
Partial Partial Partial
Simple partial, complex partial, and secondarily generalized Carbamazepine Phenytoin Valproic acid Phenobarbital Primidone Oxycarbazepine Gabapentin Lamotrigine Levetiracetam Pregabalin Lacosamide
Primary generalized Primary generalized Primary generalized
Tonic-clonic Carbamazepine Phenytoin Valproic acid Phenobarbital Primidone Lamotrigine Topiramate
Absence Ethosuximide Valproic acid Lamotrigine
Myoclonic Valproic acid Topiramate
26
Lehne, 2007, Pharmacology for Nursing Care, 6th
ed., Elsevier, p. 216
27
Monitoring Plasma Levels of AEDs
28
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.
  • 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
29
Which Drug can be Used for All Types of Seizures?
30
Which Drug can be Used for All Types of Seizures?
  1. Phenytoin
  2. Diazepam
  3. Ethosuximide
  4. Valproate

31
Phenytoin (Dilantin)Introduction
32
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
33
Phenytoin (Dilantin)Pharmacokinetics
34
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 so the dose must increase
34
35
Fosphenytoin (Cerebryx)
36
Fosphenytoin (Cerebryx)
  • Phenytoin is administered IV in a vehicle of
    pH13.
  • It precipitates readily in standard IV fluids.
  • Too rapid administration (gt50 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
37
CAUTIONName-Alikes
38
CAUTIONName-Alikes
  • (Celexa) citalopram antidepressant
  • (Celebrex) celecoxib Cox-2 NSAID
  • (Cerebryx) fosphenytoin anticonvulsant

38
39
Phenytoin Nonlinear Pharmacokinetics
40
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 down (because
    the half-life is dose dependent).

40
41
QuestionA 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
42
What Happened?
  1. The patient is not taking his medicine.
  2. The patients cytochrome P450 enzymes increased
    (were induced), so he is metabolizing the drug
    faster and levels declined.
  3. The first lab tests were in error.
  4. The patients seizures have become refractory to
    phenytoin.

43
Phenytoin Adverse Effects Neurotoxicity
44
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. Toxic levels gt20 mcg/ml?nystagmus gt30-40 mcg/ml ? ataxia/ gross motor changes (may be permanent) gt50 mcg/ml?coma Seizure diary Monitor levels Emphasize need for periodic blood tests and whenever dose changed!!! Teach to space meds and take as ordered Do not switch between chewable tablets and capsules.
44
45
Phenytoin Adverse Effects Skin
46
Phenytoin Adverse Effects Skin
Rashrisk of severe reaction Ex. Stevens-Johnson syndrome Assess skin 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
46
http//www.sjsupport.org/
47
PhenytoinOther Adverse Effects
48
Phenytoin Other Adverse Effects
Gingival hyperplasiathe gums overgrow gross but NOT LIFE-THREATENING Brush teeth bid-soft brush, floss qd Emphasize need for dental care
Decreased effects of folic acid, Ca2, vitamin K, and ? vitamin D absorption Patient assessment Emphasize need to take supplements
48
49
Carbamazepine (Tegretol Carbatrol and others)
50
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
51
Oxcarbazepine
52
Oxcarbazepine
  • As effective as carbamazepine but better
    tolerated
  • Does not cause bone marrow suppression
  • Otherwise, adverse effects are similar to
    carbamazepine

53
Which of the Following possible Adverse effects
is NOT Shared between Phenytoin and Carbamazepine?
54
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

55
Valproic Acid (Depakine and others)
56
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
57
Phenobarbital and Primidone (Mysoline)
58
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
59
Ethosuximide (Zarontin)
60
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
61
AEDs and Pregnancy
62
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 womans 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 maintain therapeutic
    levels of drug.

62
63
Effects of AEDs during Pregnancy
64
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
65
Oral Contraceptives (OCPs)
66
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
67
Discontinuing AEDs
68
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
69
Compliance
70
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
    life-long need for the drug.
  • Compliance is a major issue.

70
71
AEDsAdditional Patient Teaching
72
AEDsAdditional 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
73
Medical EmergencyStatus Epilepticus
74
Medical EmergencyStatus 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
75
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
  • Hyperthermia can lead to brain damage

75
76
Benzodiazepines (BZs)
77
Benzodiazepines (BZs)
Lorazepam (Ativan) Diazepam (Valium)
Uses Tonic-clonic status epilepticus (give IV) Both are Schedule IV controlled substances 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! 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
78
Disorders of Motor Function
78
79
Coordinated Movement
80
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 given movement.

80
81
Disorders of Motor Function
82
Disorders of Motor Function
  • Upper motoneuron lesions
  • ALS
  • Multiple Sclerosis
  • Parkinsons 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.
83
Disorders of Motor FunctionUpper Motoneuron
Lesions
84
Disorders of Motor FunctionUpper 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.

85
Disorders of Motor FunctionLower Motoneuron
Lesions
86
Disorders of Motor FunctionLower Motoneuron
Lesions
  • Disrupt communication between spinal cord and
    muscle
  • Causes a flaccid paralysis.

87
Disorders of Motor FunctionNeuromuscular
Junction Problems
88
Disorders of Motor FunctionNeuromuscular
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.

89
Disorders of Motor FunctionMyopathy
90
Disorders of Motor FunctionMyopathy
  • Disease of the muscle that makes it unable to
    respond to the nerve impulse.

91
MyopathyDisorders of Skeletal Muscle
92
MyopathyDisorders 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
93
Disorder of the NMJ Myasthenia Gravis
94
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
95
Upper Motor Neuron Diseases
96
Upper Motor Neuron Diseases
I. Amyotropic lateral sclerosis (ALS or Lou
Gehrigs disease). Also has lower motor neuron
effects the result is a spastic paralysis. II.
Multiple sclerosis III. Parkinsons disease and
other extrapyramidal problems.
96
97
Amyotrophic Lateral Sclerosis (ALS)
98
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 persons 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.)

98
Porth, Pathophysiology, Concepts of Altered
Health States, 7th ed., 2005, Lippincott, p. 1195.
99
Multiple Sclerosis (MS)
100
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
101
Multiple Sclerosis (MS)
  • 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
  • As the disease progresses, additional symptoms of
    paralysis and sensory dysfunction (numbness,
    tingling, etc.) appear.
  • Finally over a period of years, the person may
    become bed-ridden and die.
  • Treatment is by immunosuppression, which has had
    varying success.

101
102
Basal Ganglia/Extrapyramidal System
103
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.
104
Characteristics of Disorders of the Basal Ganglia
105
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
106
Types of Involuntary Movements
107
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 the face.

107
108
Parkinsons Disease (PD)
109
Parkinsons 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

109
Porth, 2007, Essential of Pathophysiology, 2nd
ed., Lippincott, p. 807
110
Characteristics of Parkinsons Disease (PD)
111
Characteristics of Parkinsons Disease (PD)
Tremor - a resting tremor that is embarrassing
for patients but doesnt 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
112
End-Stage Parkinsons Disease
113
End-Stage Parkinsons 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
114
Parkinsons Disease Therapeutic Goals
115
Parkinsons 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

116
Parkinsons Disease and Therapeutic Goals
116
117
Dopaminergic and Cholinergic Pathways and Effects
118
Dopaminergic and Cholinergic Pathways and Effects
Dopamine (DA) pathways and effects Acetylcholine (ACh) pathways and effects
Mesocortical DA affects cognition Mesolimbic DA affects emotions Striatum DA is inhibitory to GABA neurons which modulate movement Dopamine is important in psychosis there is usually too much Cortex and Limbic System ACh affects learning and memory, as well as wakefulness and attention Striatum ACh is excitatory to GABA neurons which modulate movement. Peripheral Nervous System (PNS) (Useful throughout the body) Regulation of autonomic nervous system and at PNS end organs. Excitatory transmission at the NMJ
118
119
Nigrostriatal Pathways
120
Nigrostriatal Pathways
- Neurons that originate in the substantia nigra
send their axons into the striatum
LeWitt P. N Engl J Med 20083592468-2476
121
Dopamine in PD
122
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
123
Abnormal Neurotransmission in Parkinsons Disease
124
Abnormal Neurotransmission in PD
124
Lehne, 2009, Pharmacology for Nursing Care, 7th
ed., Elsevier, p. 183.
125
Dopamine Synapse
126
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
127
Anti-Parkinson Drugs
128
Anti-Parkinson Drugs
Class Activity Drugs
Dopamine replacement ? dopamine in the synapse levodopa/carbidopa
COMT inhibitors ? dopamine in the synapse entacapone and others
MAO inhibitors ? dopamine in the synapse 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
129
Levodopa/Carbidopa
130
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
  • BUT99 converted to dopamine in periphery
  • SOcombined 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
131
Levodopa/CarbidopaPractical Use
132
Levodopa/CarbidopaPractical 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.

133
Levodopa/CarbidopaDiagram of the Effect of
Carbidopa
134
Levodopa/CarbidopaDiagram of the Effect of
Carbidopa
Lehne, 2009, Pharmacology for Nursing Care, 7th
ed., Elsevier, p. 190.
134
135
Levodopa/CarbidopaPharmacokinetics
136
Levodopa/CarbidopaPharmacokinetics
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
137
LevodopaAdverse Reactions and Nursing
138
LevodopaAdverse 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 Patient assessment Need to report any signs Dosage of levodopa/carbidopa may be decreased (but that might cause more symptoms of PD)
Personality, behavioral, mental health changes - Depression - Suicidal ideation - Hallucinations - Psychoses Patient assessment Need to report changes Advise about increased libido These effects occur because of dopamines activity in other areas of the brain, not the striatum.
138
139
LevodopaAdverse 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 administra-tion of selegiline, titrate dose carefully.
Orthostatic hypotension Cardiac dysrhythmias Monitor BP, P, EKG Teach to change positions slowly
139
140
LevodopaOn-Off Phenomenon
141
LevodopaOn-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?vECkPVTZlfP8

141
142
Levodopa/CarbidopaWearing Off
143
Levodopa/CarbidopaWearing 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
144
Dopamine Agonists
145
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 dyskinesias.

145
146
Rotigotine (Neupro)
147
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 once-daily
    application.

147
148
COMT Inhibitors
149
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)
  • Isoproterenol (a beta agonist).

149
150
Amantidine
151
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
152
Anticholinergic Agents
153
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
154
Deep Brain Stimulation for Parkinsons Disease
155
Deep Brain Stimulation for Parkinsons 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.

156
Deep Brain Stimulation
http//www.daylife.com/photo/0fz6aHe0DY2ou
157
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?
158
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?
  1. His dose of levodopa/carbidopa is to high.
  2. His dose of levodopa/carbidopa is too low
  3. He has on/off phenomenon
  4. He has wearing off phenomenon.

159
Anesthetic and Neuromuscular Blocking Agents
159
160
Types of Anesthesia
161
161
162
Balanced General Anesthesia
163
Balanced General Anesthesia
  • Results in
  • Loss of consciousness
  • Analgesia
  • Muscle relaxation
  • Because it aids in surgical procedures if the
    muscles are relaxed

163
164
The Process of General Anesthesia
165
The Process of General Anesthesia
  • Induction
  • Maintenance
  • Reversal

166
The Process of General AnesthesiaInduction
167
The Process of General AnesthesiaInduction
  • 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.

168
The Process of General AnesthesiaMaintenance
169
The Process of General AnesthesiaMaintenance
  • Maintenance The patient is maintained under
    anesthesia, often with inhalation agents.
  • If intubated (which most people are),
    neuromuscular blockade is maintained.

170
The Process of General AnesthesiaReversal
171
The Process of General AnesthesiaReversal
  • 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.

172
Intravenous Anesthetics
173
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
174
Inhalation AnestheticsDescription
175
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 cant give 100 nitrous oxide
  • Need to include some oxygen in the anesthetic
    mixture so the person will not suffocate (dont
    laugh, its happened).

175
176
Inhalation AnestheticsChart
177
Inhalation Anesthetics
Drug MAC () Analgesic Effect Effect on BP
Nitrous oxide 105 none
Halothane 0.75 ?
Desflurane 4.58 ?
Enflurane 1.68 ?
Isoflurane 1.15 ?
Sevoflurane 1.71 ?
Minimum alveolar concentration Surgical
anesthesia cannot be attained with nitrous oxide
alone.
Adapted from Lehne, 2009, Pharmacology for
Nursing Care, 7th ed., Elsevier, p. 253
177
178
Inhalation AnestheticsPharmacokinetics
179
Inhalation AnestheticsPharmacokinetics
  • 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
180
Inhalation AnestheticsEffects
181
Inhalation AnestheticsEffects
  • 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

182
Neuromuscular Blockers
183
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
184
What Types of Agents are Used for Anesthesia
Induction?
185
What Types of Agents are Used for Anesthesia
Induction?
  • Short-acting, intravenous barbiturates or
    benzodiazepines.
  • Anti-epileptic drugs
  • Inhalation anesthetics
  • - Used in the maintenance part
  • Reversal agents.

186
Local Anesthesia
187
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
188
Local AnestheticsStrategies to Prevent Diffusion
Away from the Site
189
Local AnestheticsStrategies 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
190
Local AnestheticsAdverse and Allergic Reactions
191
Local AnestheticsAdverse 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
192
Local AnestheticsUse as a Nerve Blocker
193
Local AnestheticsUse 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
194
Local AnesthesiaLidocaine
195
Local AnesthesiaLidocaine
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 The most common local anesthetic
195
196
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
    Parkinsons Disease
  • Slide 153 what is the difference between
    anticholinergic and antimuscarinic drugs
  • Slide 163 types of anesthesia in a mouth
    procedure
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