Parkinson

• Parkinson Disease (PD)

  A neurodegenerative disorder of the extrapyramidal system associated with the disruption of neurotransmission in the striatum
• Parkinson Disease

  • 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 the degeneration of the neurons that supply dopamine to the striatum
  • Second only to Alzheimer disease as the most common degenerative disease of the neurons
  • Symptoms generally appear during middle age and progress
  • No cure for motor symptoms
  • Drug therapy can maintain functional mobility for years (i.e., prolongs/improves quality of life)
• Cardinal Symptoms of Parkinson Disease

  • Dyskinesias
  • Tremor at rest
  • Rigidity
  • Postural instability
  • Bradykinesia (slowed movement)
• Must have tremor at rest and bradykinesia at time of diagnosis
• Additional Symptoms of Parkinson Disease

  • Autonomic disturbances
  • Depression
  • Psychosis and dementia
• Dopamine/Ach imbalance in Striatum

  • Proper function: Balance of between dopamine and Ach
  • Dopamine → inhibitory
  • ACh → excitatory
  • GABA → inhibitory
  • Neurons that release dopamine inhibit release of gamma-aminobutyric acid (GABA)
  • Neurons that release ACh excite the neurons release GABA
• Imbalance in Dopamine/ACh

  • Results from degeneration of the neurons that supply dopamine to the striatum
  • ↓ dopamine → ↑ ACh → excessive stimulation → release GABA → disturbed motor movement
  • Without adequate dopamine, ACh causes excessive stimulation of neurons that release gamma-aminobutyric acid
  • Overactivity of gamma-aminobutyric acid neurons contributes to the motor symptoms of PD
• Cause of degeneration

  • Uncertainty regarding the cause; may be alpha-synuclein
  • Alpha-synuclein → toxic protein that is synthesize by dopaminergic neurons
  • Normal conditions → rapidly degraded and does not accumulate, no harm
• Therapeutic Goals

  • Ideal treatment: that reverses neuronal degeneration or prevents further degeneration does not exist
  • Goal: is to improve the patient's ability to carry out the activities of daily life
  • Drug selection and dosages are determined by the extent to which PD interferes with work, dressing, eating, bathing, and other activities of daily living
• Drug Therapy for Parkinson Disease

  • Dopaminergic agents
  • Anticholinergic agents
• 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]
• Initial Treatment for Parkinson Disease

  • Mild symptoms: Monoamine oxidase-B (MAO-B) inhibitor (Selegiline or rasagiline)
  • More severe symptoms: Levodopa (combined with carbidopa) or a dopamine agonist
• Levodopa vs Dopamine Agonists

  • Levodopa is more effective than dopamine agonists
  • Long-term use of levodopa carries a higher risk for disabling dyskinesias
• Management of motor fluctuations

  • "Off" periods occur when dopamine levels ↓
  • "Off" times can be reduced with dopamine agonists, catechol-O- methyltransferase (COMT) inhibitors, and MAO-B inhibitors
  • Helps with Drug-induced dyskinesias
• No drug has yet been proven to provide neuroprotective effects for people with PD
• MAO-B inhibitors have provided neuroprotective effects in animal studies
• Dopamine agonists have demonstrated neuroprotective effects in laboratory studies
• Levodopa

  • Only given in combination with carbidopa or carbidopa/entacapone
  • Highly effective, but benefits diminish over time
  • Orally administered; rapidly absorbed from small intestine
  • Food delays absorption
  • High-protein foods reduce therapeutic effects
• Use of Levodopa in PD

  • Diagnosis of PD questioned if levodopa fails
  • Several months of treatment needed for full therapeutic response
  • Symptoms well controlled for first 2 years
  • Return to pretreatment state at the end of 5 years
• Acute loss of effect of Levodopa

  • Gradual loss—"wearing off"—develops near the end of the dosing interval and indicates that drug levels have declined to a subtherapeutic value
  • Wearing off can be minimized by shortening the dosing interval, giving a drug that prolongs levodopa's plasma half-life (e.g., entacapone/ COMT inhibitors), or giving a direct-acting dopamine agonist
• Mechanism of action of Levodopa

  • Reduces symptoms by ↑ dopamine synthesis in the striatum → carries across BBB → enters brain via active transport system
  • In the brain: Uptake into the remaining dopaminergic nerve terminals that remain in the striatum
  • No direct effects of its own → converted to dopamine → its active form
  • Restore a proper balance between dopamine and ACh
  • The activity of decarboxylases is enhanced by pyridoxine (vitamin B6)
• Adverse effects of Levodopa

  • Nausea and vomiting
  • Cardiovascular
  • Postural hypotension
  • Darkens sweat and urine
  • Activates malignant melanoma
  • Dyskinesias
• Severe Adverse Effects of Levodopa

  • Psychosis
  • Visual hallucinations
  • Vivid dreams or nightmares
  • Paranoid ideation
• Central Nervous System Adverse Effects of Levodopa

  • Anxiety and agitation
  • Memory and cognitive impairment
  • Insomnia and nightmares
  • Problems with impulse control
  • Behavioral changes (promiscuity, gambling, binge eating, and alcohol abuse)
• Drug Interactions with Levodopa

  • First-generation antipsychotic drugs (e.g., chlorpromazine, haloperidol)
  • MAO inhibitors
  • Anticholinergic drugs
  • Pyridoxine (vitamin B6)
• Disadvantages of Levodopa

  • Carbidopa has no adverse effects of its own
  • Any adverse responses from carbidopa/levodopa are the result of the potentiating of the effects of levodopa
  • Levodopa + carbidopa → abnormal movements and psychiatric disturbances can occur sooner and be more intense than with levodopa alone
• Dopamine Agonists

  • First-line drugs for PD
  • Direct activation of dopamine receptors in the striatum
  • Less effective than levodopa
  • Not dependent on enzymatic conversion to be active
  • Does not compete with dietary proteins
  • Lower incidence of response failure
  • Less likely to cause dyskinesias
• Types of Dopamine Agonists

  • Nonergot derivatives
  • Pramipexole [Mirapex]
  • Ropinirole [Requip]
• Pramipexole

  • Used alone in early PD or with levodopa in advancing PD
  • Maximal benefits take several weeks to develop
  • Adverse effects: Nausea, dizziness, daytime somnolence, insomnia, constipation, weakness, and hallucinations (monotherapy); Orthostatic hypotension, dyskinesias, and increase in hallucinations (combined with levodopa)
  • Rare instances of pathologic gambling and other compulsive self-rewarding behaviors
• Ropinirole

  • Highly selective for D2 and D3 receptors
  • Uses: PD (monotherapy for early PD, adjunct with levodopa for advance PD), Restless leg syndrome
  • Adverse Effects: Nausea, dizziness, somnolence, hallucinations, rarely sleep attacks (monotherapy); Dyskinesias, hallucinations, postural hypotension (combo with levodopa)
• Dopamine agonists

  • Less likely to cause dyskinesias
• Types of dopamine agonists

  • Nonergot derivatives - Pramipexole, Ropinirole, Rotigotine, and Apomorphine
  • Derivatives of ergot - Bromocriptine and Cabergoline
• Pramipexole

  • Used alone in early PD
  • Used with levodopa in advancing PD
  • Maximal benefits take several weeks to develop
• Adverse effects of Pramipexole

  • Monotherapy: Nausea, dizziness, daytime somnolence, insomnia, constipation, weakness, and hallucinations
  • Combined with levodopa: Orthostatic hypotension, dyskinesias, and increase in hallucinations
  • Rare instances of pathologic gambling and other compulsive self-rewarding behaviors
• Ropinirole

  • Highly selective for D2 and D3 receptors
  • Used for PD and Restless leg syndrome
• Adverse effects of Ropinirole

  • Monotherapy: Nausea, dizziness, somnolence, hallucinations
  • Rarely sleep attacks
  • Combined with levodopa: Dyskinesias, hallucinations, postural hypotension, compulsive gambling, shopping, eating, and hypersexuality
  • do not use during pregnancy
• Rotigotine

  • Used for PD (early to advanced) and Restless leg syndrome (moderate to severe)
• Adverse effects of Rotigotine

  • CNS and neuromuscular: Sleeping disorders, dizziness, headache
  • Dose-related hypotension and dyskinesia
  • Orthostatic hypotension
  • Peripheral edema
  • Nausea/vomiting
  • Skin reactions at site of application
  • Hyperhidrosis (excessive sweat)
• Apomorphine

  • Acute treatment of hypomobility during "off" episodes with advanced PD
  • Not given by mouth, not indicated for routine PD management
  • Derivative of morphine with no opioid effects