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Chapter 21. Drugs for Parkinson’s Disease. Parkinson’s Disease. Parkinson’s disease (PD) is a neurodegenerative disorder of the extrapyramidal system associated with disruption of neurotransmission in the striatum Characterized by dyskinesias and akinesia - PowerPoint PPT Presentation
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Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Chapter 21
Drugs for Parkinson’s Disease
2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Parkinson’s Disease
Parkinson’s disease (PD) is a neurodegenerative disorder of the extrapyramidal system associated with disruption of neurotransmission in the striatum 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.
3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Parkinson’s Disease
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).
4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Cardinal Symptoms of PD
Dyskinesias Tremor at rest Rigidity Postural instability Bradykinesia (slowed movement) Tremor
In addition to motor symptoms Autonomic disturbances Depression Psychosis and dementia
5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Dopamine/ACh Imbalance in Striatum
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.
6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Fig. 21-1. A model of neurotransmission in the healthy striatum and parkinsonian striatum.
7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Parkinson’s Disease
Therapeutic goals 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.
8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Drug Therapy for Parkinson’s Disease
Two major categories 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)
9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Drug Therapy for Parkinson’s Disease
Levodopa (drug holidays recommended) Levodopa/carbidopa Dopamine agonists
Pramipexole (Mirapex) Entacapone (Comtan) Amantadine (Symmetrel) Selegiline (Eldepryl, Carbex)
10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Dopaminergic Agents
Mechanisms of action 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
11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Drug Selection: Initial Treatment
Mild symptoms: MAO-B inhibitor Selegiline or rasagiline
More severe symptoms: levodopa or a dopamine agonist Levodopa more effective than dopamine agonists,
but long-term use carries a higher risk for disabling dyskinesias
Management of motor fluctuations “Off” times (can be reduced with dopamine
agonists, COMT inhibitors, and MAO-B inhibitors) Drug-induced dyskinesias
12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Fig. 21-2. Steps leading to alteration of CNS function by levodopa.
13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Fig. 21-3. Conversion of levodopa to dopamine.
14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Levodopa
Only given in combination with carbidopa or carbidopa/entacapone
Highly effective, but benefits diminish over time
Orally administered, rapid absorption from small intestine 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.
15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Levodopa
Adverse effects 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
16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Carbidopa
Advantages 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)
17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Fig. 21-4. Fate of levodopa in the presence and absence of carbidopa.
18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Dopamine Agonists
First-line drugs for PD Direct activation of dopamine receptors in striatum Comparison with levodopa
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
Derivatives of ergot Nonergot derivatives
19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Nonergot Dopamine Agonists
Pramipexole (Mirapex) 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
20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
COMT Inhibitors
Inhibit metabolism of levodopa in the periphery
No direct therapeutic effects of their own Two COMT inhibitors available
Entacapone (safer and more effective) Tolcapone
21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Entacapone
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
22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Levodopa/Carbidopa/Entacapone
Fixed-dose combinations sold as Stalevo More convenient than taking separate doses Costs a little less Disadvantage
Available only in immediate-release tablets Available in only three strengths
23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
MAO-B Inhibitors
Considered second- and third-line drugs for treatment of PD
Combination with levodopa – can reduce the wearing-off effect
Selegiline
24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Selegiline (Eldepryl, Zelapar)
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 Monotherapy: insomnia
Drug interactions: levodopa
25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Nonmotor Symptoms and Their Management
90% of patients develop nonmotor symptoms (autonomic disturbances, depression, dementia, and psychosis).
Depression Amitriptyline: only effective drug TCA Anticholinergic effects that can exacerbate
dementia Antiadrenergic effects that can exacerbate
hypotension