1. Drugs for Parkinson’s Disease1

2. 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. 2

3. 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). 3

4. 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 4

5. 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. 5

6. Fig. 21-1. A model of neurotransmission in the healthy striatum and parkinsonian striatum.6

7. 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. 7

8. 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) 8

9. Drug Therapy for Parkinson’s Disease
Levodopa (drug holidays recommended)
Levodopa/carbidopa
Dopamine agonists
Pramipexole (Mirapex)
Entacapone (Comtan)
Amantadine (Symmetrel)
Selegiline (Eldepryl, Carbex) 9

10. 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 10

11. 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 11

12. Fig. 21-2. Steps leading to alteration of CNS function by levodopa.12

13. Fig. 21-3. Conversion of levodopa to dopamine.13

14. 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. 14

15. Levodopa Adverse effects Drug holidays
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 15

16. Carbidopa Advantages Levodopa/carbidopa (Sinemet, Paracopa)
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) 16

17. Fig. 21-4. Fate of levodopa in the presence and absence of carbidopa.17

18. 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 18

19. 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 19

20. 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 20

21. 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 21

22. 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 22

23. MAO-B Inhibitors
Considered second- and third-line drugs for treatment of PD
Combination with levodopa – can reduce the wearing-off effect
Selegiline 23

24. 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 24

25. 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 25