Download Chapter 16 Cholinesterase Inhibitors

Drugs for Parkinson’s Disease
Parkinson’s Disease
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Parkinson’s disease (PD) is a neurodegenerative
disorder of the extrapyramidal system associated
with disruption of neurotransmission in the striatum
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Characterized by dyskinesias and akinesia
Proper function of the striatum requires a balance
between the neurotransmitters dopamine and
acetylcholine (ACh)
 Imbalance between dopamine and ACh results from
degeneration of the neurons that supply dopamine to
the striatum.
Parkinson’s Disease
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Affects more than 1 million Americans
Second only to Alzheimer’s disease as the
most common degenerative disease of
neurons
Symptoms generally appear in middle age
and progress
No cure for motor symptoms
Drug therapy can maintain functional mobility
for years (prolongs/improves quality of life).
Cardinal Symptoms of PD
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Dyskinesias
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Tremor at rest
Rigidity
Postural instability
Bradykinesia (slowed movement)
Tremor
In addition to motor symptoms
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Autonomic disturbances
Depression
Psychosis and dementia
Dopamine/ACh
Imbalance in Striatum
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Imbalance results from degeneration of the
neurons that supply dopamine to the striatum.
Without adequate dopamine, ACh causes
excessive stimulation of GABA-releasing
neurons.
Overactivity of GABA neurons contributes to
the motor symptoms of PD.
Uncertain of cause of degeneration—may be
alpha-synuclein.
Fig. 21-1. A model of neurotransmission in the healthy striatum
and parkinsonian striatum.
Parkinson’s Disease
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Therapeutic goals
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Ideal treatment (reverse neuronal degeneration or
prevent further degeneration) does not exist.
Goal is to improve patient’s ability to carry out
activities of daily life.
Drug selection and dosages are determined by
extent to which PD interferes with work, dressing,
eating, bathing, and other activities of daily living.
Drug Therapy for
Parkinson’s Disease
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Two major categories
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Dopaminergic agents
• By far the most commonly used drugs for PD
• Promote activation of dopamine receptors
• Levodopa (Dopar)
 Anticholinergic agents
• Prevent activation of cholinergic receptors
• Benztropine (Cogentin)
Drug Therapy for
Parkinson’s Disease
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Levodopa (drug holidays recommended)
Levodopa/carbidopa
Dopamine agonists
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Pramipexole (Mirapex)
Entacapone (Comtan)
Amantadine (Symmetrel)
Selegiline (Eldepryl, Carbex)
Dopaminergic Agents
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Mechanisms of action
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Levodopa: promotes dopamine synthesis
Dopamine agonists: stimulate dopamine receptors
directly
Selegiline: inhibits dopamine breakdown
Amantadine: promotes dopamine release
COMT inhibitors: enhance effects of levodopa by
blocking its degradation
Drug Selection: Initial Treatment
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Mild symptoms: MAO-B inhibitor
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More severe symptoms: levodopa or a
dopamine agonist
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Selegiline or rasagiline
Levodopa more effective than dopamine agonists,
but long-term use carries a higher risk for
disabling dyskinesias
Management of motor fluctuations
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“Off” times (can be reduced with dopamine
agonists, COMT inhibitors, and MAO-B inhibitors)
Drug-induced dyskinesias
Fig. 21-2. Steps leading to alteration of CNS function by levodopa.
Fig. 21-3. Conversion of levodopa to dopamine.
Levodopa
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Only given in combination with carbidopa or
carbidopa/entacapone
Highly effective, but benefits diminish over
time
Orally administered, rapid absorption from
small intestine
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Food delays absorption.
Neutral amino acids compete with levodopa for
intestinal absorption and for transport across
blood-brain barrier.
High-protein foods will reduce therapeutic effects.
Levodopa
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Adverse effects
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Nausea and vomiting
Dyskinesias
Cardiovascular effects
Psychosis
May darken sweat and urine
Can activate malignant melanoma
Drug holidays
Drug interactions: first-generation antipsychotics,
MAOIs, anticholinergics, pyridoxine
Food interactions: protein and vitamins with
pyridoxine
Carbidopa
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Advantages
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No adverse effects of its own
Increases available levodopa in the CNS and
allows for 75% decrease in levodopa dosage;
therefore, reduces cardiovascular and GI adverse
effects
Effects come mainly from levodopa when given in
combination.
Levodopa/carbidopa (Sinemet, Paracopa)
Carbidopa alone (Lodosyn)
Fig. 21-4. Fate of levodopa in the presence and absence of carbidopa.
Dopamine Agonists
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First-line drugs for PD
Direct activation of dopamine receptors in striatum
Comparison with levodopa
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Less effective than levodopa
Not dependent on enzymatic conversion to be active
Do not compete with dietary proteins
Lower incidence of response failure and less likely to cause
dyskinesias
Two types of dopamine agonists
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Derivatives of ergot
Nonergot derivatives
Nonergot Dopamine Agonists
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Pramipexole (Mirapex)
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Used alone in early PD and with levodopa in
advancing PD
Maximal benefits take several weeks to develop.
Adverse effects
• Monotherapy – nausea, dizziness, daytime somnolence,
insomnia, constipation, weakness, and hallucinations
• Combined – orthostatic hypotension and dyskinesias and
increase in hallucinations
• Rare instances of pathologic gambling and other
compulsive self-rewarding behaviors
COMT Inhibitors
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Inhibit metabolism of levodopa in the
periphery
No direct therapeutic effects of their own
Two COMT inhibitors available
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Entacapone (safer and more effective)
Tolcapone
Entacapone
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Selective, reversible inhibitor of COMT
Only for use with levodopa
Inhibits metabolism of levodopa in the intestines and
peripheral tissues
Prolongs time that levodopa is available to the brain
Increases levodopa availability by inhibiting COMT,
which decreases production of levodopa metabolites
that compete with levodopa for transport
Adverse effects: from increasing levodopa levels
Levodopa/Carbidopa/Entacapone
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Fixed-dose combinations sold as Stalevo
More convenient than taking separate doses
Costs a little less
Disadvantage
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Available only in immediate-release tablets
Available in only three strengths
MAO-B Inhibitors
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Considered second- and third-line drugs for
treatment of PD
Combination with levodopa – can reduce the
wearing-off effect
Selegiline
Selegiline
(Eldepryl, Zelapar)
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Monotherapy or used with levodopa
Modest improvement in motor function
Causes selective, irreversible inhibition of
type B monoamine oxidase (MAO-B)
Can suppress destruction of dopamine
derived from levodopa and prolong the
effects of levodopa
Adverse effects
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Monotherapy: insomnia
Drug interactions: levodopa
Nonmotor Symptoms and
Their Management
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90% of patients develop nonmotor symptoms
(autonomic disturbances, depression,
dementia, and psychosis).
Depression
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Amitriptyline: only effective drug
TCA
Anticholinergic effects that can exacerbate
dementia
Antiadrenergic effects that can exacerbate
hypotension