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Seizures
What is a Seizure?
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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
Provoked vs. Unprovoked Seizures
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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
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Seizures
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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.
Classification of Seizures
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Classification of Seizures
• Partial seizures
• Generalized seizures
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Classification of SeizuresPartial Seizures
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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.
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Classification of SeizuresGeneralized Seizures
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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.
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The Best Definition for a Seizure that Involves the Entire Brain is
Which of the Following?
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The Best Definition for a Seizure that Involves the Entire Brain is Which of the Following?
1. A partial seizure2. An atonic seizure3. A generalized
seizure4. A tonic-clonic
seizure.
A p
artia
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An a
tonic
sei
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A g
ener
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.
A to
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...
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Microglioma
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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
Antiepileptic Drugs (AEDs): Mechanism of Action
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Antiepileptic Drugs (AEDs): Mechanism of ActionAll 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
Resting Potential
Threshold Potential-no AED
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.
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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.
GABAergic Neurotransmission
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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
Clinical Choice of AEDs
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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.
Types of Anti-Epileptic Drugs
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Seizure Type
Drugs Used for Treatment
Traditional AEDs Newer AEDs
PartialSimple partial, complex partial, and secondarily generalized
Carbamazepine
Phenytoin
Valproic acid
Phenobarbital
Primidone
Oxycarbazepine
Gabapentin
Lamotrigine
Levetiracetam
Pregabalin
Lacosamide
Primary generalizedTonic-clonic Carbamazepine
Phenytoin
Valproic acid
Phenobarbital
Primidone
Lamotrigine
Topiramate
Absence Ethosuximide
Valproic acid
Lamotrigine
Myoclonic Valproic acid TopiramateLehne, 2007, Pharmacology for Nursing Care, 6th ed., Elsevier, p. 216
Monitoring Plasma Levels of AEDs
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Monitoring Plasma Levels of AEDsI. 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.
Which Drug can be Used for All Types of Seizures?
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Which Drug can be Used for All Types of Seizures?
1. Phenytoin2. Diazepam3. Ethosuximide4. Valproate
Phen
ytoi
n
Dia
zepam
Eth
osuxi
mid
e
Val
proat
e
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Phenytoin (Dilantin)Introduction
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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
Phenytoin (Dilantin)Pharmacokinetics
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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
Phenytoin (Dilantin)Pharmacokinetics
Fosphenytoin (Cerebryx®)
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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.
CAUTION:Name-Alikes
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CAUTION:Name-Alikes
• (Celexa®) citalopram = antidepressant• (Celebrex®) celecoxib = Cox-2 NSAID• (Cerebryx®) fosphenytoin = anticonvulsant
Phenytoin Nonlinear Pharmacokinetics
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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).
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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?
What Happened?
1. The patient is not taking his medicine.
2. The patient’s 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 patient’s seizures have
become refractory to phenytoin.
The
patie
nt is
...
The
patie
nt’s
...
The
first
lab ..
.
The
patie
nt’s
...
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Phenytoin Adverse Effects: Neurotoxicity
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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:
>20 mcg/ml→nystagmus
>30-40 mcg/ml → ataxia/ gross motor changes (may be permanent)
>50 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.
Phenytoin Adverse Effects: Skin
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Phenytoin Adverse Effects: SkinRash—risk 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.
http://www.sjsupport.org/See carbamazepine-induced SJS under “Interesting Articles” on Blackboard
PhenytoinOther Adverse Effects
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Phenytoin: Other Adverse Effects
Gingival hyperplasia—the gums overgrow; gross but NOT LIFE-
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
Carbamazepine (Tegretol® Carbatrol® and others)
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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
Oxcarbazepine
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Oxcarbazepine• As effective as carbamazepine but better
tolerated– Does not cause bone marrow suppression
• Otherwise, adverse effects are similar to carbamazepine
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Which of the Following possible Adverse effects is NOT Shared
between Phenytoin and Carbamazepine?
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Which of the Following possible Adverse effects is NOT Shared between Phenytoin and Carbamazepine?
1. Stevens-Johnson syndrome
2. Ataxia/neurologic effects.
3. Aplastic anemia4. Mild sedation
Ste
vens-
John
so...
Ata
xia/
neuro
lo...
Apla
stic
anem
i...
Mild
sed
atio
n
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Valproic Acid (Depakine® and others)
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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.
Phenobarbital and Primidone (Mysoline®)
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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.
Ethosuximide (Zarontin®)
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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.
AEDs and Pregnancy
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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 maintain therapeutic levels of drug.
Effects of AEDs during Pregnancy
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Effects of AEDs during Pregnancy•Phenytoin and other AEDs alter folate metabolism, so it isrecommended 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.
Oral Contraceptives (OCPs)
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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.
Discontinuing AEDs
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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.
Compliance
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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.
AED’sAdditional Patient Teaching
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AED’sAdditional 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.
Medical EmergencyStatus Epilepticus
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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
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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
Benzodiazepines (BZ’s)
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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!
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Disorders of Motor Function
Coordinated Movement
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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.
Disorders of Motor Function
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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
Porth, Pathophysiology, Concepts of Altered Health States, 7th ed., 2005, Lippincott, p. 1195.
Disorders of Motor FunctionUpper Motoneuron Lesions
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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.
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Disorders of Motor FunctionLower Motoneuron Lesions
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Disorders of Motor FunctionLower Motoneuron Lesions
• Disrupt communication between spinal cord and muscle
• Causes a flaccid paralysis.
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Disorders of Motor FunctionNeuromuscular Junction
Problems
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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.
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Disorders of Motor FunctionMyopathy
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Disorders of Motor FunctionMyopathy
• Disease of the muscle that makes it unable to respond to the nerve impulse.
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MyopathyDisorders of Skeletal Muscle
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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
Disorder of the NMJ Myasthenia Gravis
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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.
Upper Motor Neuron Diseases
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Upper Motor Neuron DiseasesI. 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.
Amyotrophic Lateral Sclerosis (ALS)
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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.
Multiple Sclerosis (MS)
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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.
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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 bed-ridden and die.
H. Treatment is by immunosuppression, which has had varying success.
Basal Ganglia/Extrapyramidal System
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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.
McCance & Heuther, Pathophysiology: The Biologic Basis for Disease in Adults & Children, 4th ed., 2002, Mosby, p.373.
Characteristics of Disorders of the Basal Ganglia
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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
Types of Involuntary Movements
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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.
Parkinson’s Disease (PD)
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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
– ParkinsonismPorth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 807
Characteristics of Parkinson’s Disease (PD)
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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.
End-Stage Parkinson’s Disease
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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.
Parkinson’s Disease Therapeutic Goals
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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
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Parkinson’s Disease and Therapeutic Goals
Dopaminergic and Cholinergic Pathways and Effects
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Dopaminergic and Cholinergic Pathways and EffectsDopamine (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
Nigrostriatal Pathways
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Nigrostriatal Pathways
LeWitt P. N Engl J Med 2008;359:2468-2476
- Neurons that originate in the substantia nigra send their axons into the striatum
Dopamine in PD
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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).
Abnormal Neurotransmission in Parkinson’s Disease
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Abnormal Neurotransmission in PD
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 183.
Dopamine Synapse
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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.
Anti-Parkinson Drugs
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Anti-Parkinson DrugsClass 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)
Levodopa/Carbidopa
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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.
Levodopa/CarbidopaPractical Use
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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.
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Levodopa/CarbidopaDiagram of the Effect of
Carbidopa
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Levodopa/CarbidopaDiagram of the Effect of Carbidopa
Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 190.
Levodopa/CarbidopaPharmacokinetics
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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
LevodopaAdverse Reactions and Nursing
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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 dopamine’s activity in other areas of the brain, not the striatum.
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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
LevodopaOn-Off Phenomenon
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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?v=ECkPVTZlfP8
Levodopa/CarbidopaWearing Off
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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.
Dopamine Agonists
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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.
Rotigotine (Neupro)
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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.
COMT Inhibitors
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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).
Amantidine
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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.
Anticholinergic Agents
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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.
Deep Brain Stimulation for Parkinson’s Disease
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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?
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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 phenomenon4. He has wearing off
phenomenon.
His
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Anesthetic and Neuromuscular Blocking Agents
Types of Anesthesia
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In ha la tion P a re n te ra l
G e ne ra l L o ca l
A n es the s ia
Balanced General Anesthesia
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Balanced General Anesthesia
Results in:• Loss of consciousness• Analgesia• Muscle relaxation– Because it aids in surgical procedures if the
muscles are relaxed
The Process of General Anesthesia
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The Process of General Anesthesia
• Induction
• Maintenance
• Reversal
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The Process of General AnesthesiaInduction
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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.
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The Process of General Anesthesia
Maintenance
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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.
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The Process of General AnesthesiaReversal
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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.
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Intravenous Anesthetics
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Intravenous AnestheticsI. 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.
Inhalation AnestheticsDescription
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Inhalation AnestheticsDescription
•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).
Inhalation AnestheticsChart
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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
Inhalation AnestheticsPharmacokinetics
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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.
Inhalation AnestheticsEffects
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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
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Neuromuscular Blockers
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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.
What Types of Agents are Used for Anesthesia Induction?
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What Types of Agents are Used for Anesthesia Induction?
1. Short-acting, intravenous barbiturates or benzodiazepines.
2. Anti-epileptic drugs3. Inhalation anesthetics
- Used in the maintenance part
4. Reversal agents.
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Local Anesthesia
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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
Local AnestheticsStrategies to Prevent Diffusion
Away from the Site
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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
Local AnestheticsAdverse and Allergic Reactions
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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.
Local AnestheticsUse as a Nerve Blocker
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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.
Local AnesthesiaLidocaine
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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
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
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