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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

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Chapter 21

Chapter 21

Drugs for Parkinson’s Disease

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

    • 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 disease1
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).

Cardinal symptoms of pd
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
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.

Chapter 21

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

Parkinson s disease2
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.

Drug therapy for parkinson s disease
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 disease1
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
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
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

Chapter 21

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

Chapter 21

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


  • 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.


  • 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


  • 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)

Chapter 21

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

Dopamine agonists
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
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
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


  • 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
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
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
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