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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.

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
  • 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)
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