Chapter 21

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.



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

Dyskinesias Tremor at rest Rigidity Postural instability Bradykinesia (slowed movement) Tremor

In addition to motor symptoms Autonomic disturbances Depression Psychosis and dementia


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.


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



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.


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)


Drug Therapy for Parkinson’s Disease

Levodopa (drug holidays recommended) Levodopa/carbidopa Dopamine agonists

Pramipexole (Mirapex) Entacapone (Comtan) Amantadine (Symmetrel) Selegiline (Eldepryl, Carbex)


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


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


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


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


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.


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


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)


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


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


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


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


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


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


MAO-B Inhibitors

Considered second- and third-line drugs for treatment of PD

Combination with levodopa – can reduce the wearing-off effect

Selegiline


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


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

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