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5. HDS Neuro Psych > Parkinson's Medications > Flashcards

Parkinson's Medications Flashcards

1
Q

Parkinson’s Disease

Overview

A

A disease of the extra-pyramidal motor system in the brain ⇒ coordinates motor movements, particularly fine motor movements

Caused by a loss of dopaminergic neurons in the substantia nigra

Characteristics:

  • Chronic, progressive
  • Begins in middle/late life → progressive disability
  • Affects all ethnic groups
  • Equal gender distribution
  • Age group
    • 65-74 years of age: 15%
    • > 85 years: > 50%
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2
Q

Basal Ganglia

Direct Pathway

A
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3
Q

Basal Ganglia

Indirect Pathway

A
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4
Q

Basal Ganglia

Dopamine Effects

A
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5
Q

Dopamine Receptors

A
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6
Q

Parkinson’s

Neuroanatomical Correlates

A
  • Characterized by a progressive degeneration of the nigrostriatal pathway
  • Early in the disease ⇒ remaining neurons fire faster, ↑ receptor density on post-synaptic striatal tissue
  • When sx evident ⇒ almost 80% depletion of dopamine in the target area
  • Loss of striatal dopamine ⇒ ∆ activity of internal globus pallidus → projections to thalamus → projections to cortex ⇒ controls movement
  • Activity influenced by the direct pathway (enables movement) or the indirect pathway (inhibits movement)
  • Dopamine stimulates the direct pathway and inhibits the indirect pathway
  • Together these pathways result in purposeful movement
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7
Q

Parkinson’s Disease

Causes

A
  • Most cases are idiopathic
    • ? Environmental toxins related to free radicals
  • Carbon monoxide, manganese, or oxidative damage
    • MPTP drug destroys dopaminergic neurons ⇒ Parkinson-like sx
      • Paraquat (insecticide) ⇒ same effect as MPTP
    • MPTP → MPP+ by monoamine oxidase
    • MPP+ taken up by nerve terminals through dopamine reuptake system
    • ⊗ Complex I of ETC ⇒ ⊗ oxidative phosphorylation ⇒ ↑ oxidative stress/free radicals ⇒ death of neurons in nigrostriatal pathway
  • Antipsychotic drugs ⇒ reversible form of Parkinsonism
  • Genetic: mutation of α-synuclein and parkin, among others
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8
Q

Parkinson’s Disease

Clinical Manifestations

A
  • Resting tremor
    • Fine persistent involuntary tremor, particularly in the hands, fingers and feet
    • One typical tremor is the “pill-rolling tremor”
  • Rigidity of the striated musculature due to ↑ muscle tone
    • Plastic rigidity: move the afflicted limb into a new position where it will remain
  • Bradykinesia or akinesia
    • Bradykinesia: slowed ability to initiate movement
    • Akinesia: lack of ability to initiate movement
  • Absence of facial expression, shuffling gait, drooling, toneless speech
  • Difficulty in initiation of walking, small shuffling steps, no arm swing, stopping difficulty
  • Cognitive defect similar to Alzheimer’s
  • Depression
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9
Q

Treatment Strategies

A
  • Restore DA levels by administering precursors
  • Replace DA by adding receptor agonists
  • Dopamine releasing agents
  • Anticholinergics
  • Stabilize DA w/ monoamine oxidase inhibitor
  • Stabilize DA w/ COMT inhibitor
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10
Q

Dopamine Precursors

A

L-DOPA/Carbidopa (Sinemet, Atamet)

  • Goal to restore dopamine levels
  • L-DOPA crosses BBB (has both a ⊕ and ⊖ charge)
    • Dopamine does not cross BBB
    • L-DOPA → dopamine by neurons ⇒ stored in vesicles ⇒ released
  • Severity of disease determines pt response
    • Need neurons to convert L-DOPA to DA
  • Improvement onset may take weeks, optimal benefit 1-2 months
  • Order of sx improvement:
    • Mood and vigor → bradykinesia and akinesia → tremor
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11
Q

L-DOPA/Carbidopa

Indications

A
  • Tolerable doses diminish with time
  • Efficacy also diminishes with time
  • L-DOPA is most effective at diminishing bradykinesia, but also improves other symptoms
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12
Q

L-DOPA/Carbidopa

Pharmacokinetics

A
  • L-DOPA is rapidly absorbed from the intestine
    • Rate influenced by gastric emptying rate, local pH, food
  • ~1-3% of L-DOPA reaches the brain; the rest is metabolized by DOPA decarboxylase
  • Co-admin w/ peripheral DOPA decarboxylase inhibitor (Carbidopa)
    • ↑ plasma T½ ⇒ ↓ needed dose ⇒ ↓ adverse effects
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13
Q

L-DOPA/Carbidopa

Adverse Effects

A

All patients will develop adverse effects

Short-term effects

  • Anorexia, nausea and vomiting (~20%)
    • Caused by activation of chemoreceptor trigger zone in the medulla
    • ↓ by giving the drug with or after meals or by dividing the dose
    • Tolerance develops
  • Orthostatic hypotension
    • Centrally mediated
    • Tolerance develops
  • Tachycardia
    • Due to dopa → NE
    • Less prominent w/ Carbidopa

Long-term effects requiring alteration in dose

  • Dyskinesias (80%)
    • Facial grimacing, restless feet syndrome, and stereotyped behavior
    • Choreoform movements
    • Titrate up dose
    • May be fleeting or severely debilitating
    • No tolerance
      • A previously tolerated dose of L-dopa can induce dyskinesias later
  • Psychiatric and behavioral side effects
    • Nightmares or anxiety
    • Paranoia, hallucinations and mania
    • D/t overstimulation of dopamine receptors
    • Reduction in dose can alleviate the problem
  • Aphrodisiac effect
    • May be related to improved mood
    • DA also involved in hypothalamic/pituitary function
  • Response fluctuations, on-off phenomena
    • L-DOPA intake timing (wearing-off, end-of-dose akinesia)
    • ↓ Therapeutic window and ↓ half-life of L-DOPA as disease progresses
    • ↓ ability to store DA
    • Manage w/ dopamine agonists, alteration of diet, or using slow-release L-DOPA
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14
Q

L-DOPA/Carbidopa

Interactions and Contraindications

A
  • Drug Interactions:
    • Combo w/ monoamine oxidase A inhibitors ⇒ hypertensive crisis
  • Contraindications:
    • Psychotic patients
    • Open-angle glaucoma
    • Cardiac disease
    • Peptic ulcer disease
    • Hx of melanoma
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15
Q

Sinemet CR (controlled release)

A
  • Chronic L-DOPA use for many years ⇒ drug begins to wear off before the next dose
  • Change to controlled release formulation
  • Short-term release of DOPA improves motor symptoms in 30 min
  • Controlled release provides DOPA over a prolonged period
  • You may want to combine short acting and controlled release
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16
Q

Dopamine Agonists

A
  • Agents directly activate dopamine receptors
  • Sometimes used as a first line drug b/c there may be less dyskinesias
  • Begin with low doses of Sinemet and then add the dopamine agonist
17
Q

Bromocriptine (D2, D3)

Overview

A

Dopamine agonist ⇒ ergot alkaloid

  • It is administered orally
  • Excreted in the bile and feces
  • Indications:
    • Bromocriptine is considered a first line drug for Parkinson’s
    • Lower doses ⇒ used to treat hyperprolactinemia
  • Compared to L-DOPA there is less chance of response fluctuations and dyskinesia
18
Q

Bromocriptine (D2, D3)

Adverse Effects

A
  • Cardiovascular effects
    • Postural hypotension
    • Cardiac arrhythmias ⇒ stop treatments
    • All Ergots:
    • Erythromelalgia (painful swollen feet)
    • Digital vasospasm (feet and hands become cool and dusky)
  • Gastrointestinal
    • Anorexia, nausea, and vomiting
      • All reduced when taken with food
    • Constipation, indigestion, peptic ulceration, and reflux esophagitis
  • Dyskinesia
    • Less than L-DOPA/carbidopa
  • Mental disturbance
    • Hallucinations are more common with bromocriptine than L-DOPA
      • Mediated by D3 receptors
    • Compulsive behaviors such as gambling, hypersexuality and excessive shopping
    • Sudden sleep episodes
    • Hypoprolactinemia
  • Fibrosis
    • Membrane lining of body organs becomes thickened or scarred
19
Q

Non-Ergot

Dopamine Agonists

A

Pramipexole (D3>D2) and Ropinirole (D2, D3)

  • More widely used than the ergots
  • Provide greater relief with fewer adverse effects
    • More likely to cause sudden sleep episodes
    • Compulsive behavior
    • Dyskinesia
    • Hallucinations
    • Cardiovascular side effects are less common, but hypotension does occur
20
Q

Dyskinesias

Effects of T½

A

Prolonged stimulation of dopamine receptors leads to fewer dyskinesias.

21
Q

Selegiline

MOA & Indications

A
  • Monoamine oxidase B inhibitor
    • Retards the breakdown of dopamine
    • Prolongs the effect of DOPA
  • Currently used as an adjunctive therapy
    • DOPA dose reduction
    • Reduce mild on-off phenomena and wearing off phenomena
    • Could enhance the adverse effects of L-DOPA
22
Q

Selegiline

Adverse Effects

A

Selegiline @ doses used for Parkinson’s:

Predominantly inhibits monoamine oxidase B

Minimal effect on monoamine oxidase A isozyme

  • Responsible for tyramine degradation ⇒ ↓ potential interaction with tyramine containing foods ⇒ ↓ chance of a hypertensive crisis
  • Responsible for serotonin inactivation
    • Even low-dose Selegiline is contraindicated in pts taking agents that cause the release of serotonin ⇒ potential for serotonin syndrome
    • SSRI, TCAs, meperidine and other opiates, dextromethorphan, tryptophan
  • Selegiline is metabolized to L-methamphetamine and L-amphetamine ⇒ may cause insomnia
23
Q

Rasagiline

A

An irreversible monoamine oxidase B inhibitor.

Is not metabolized to methamphetamine.

24
Q

Amantadine (Symmetrel)

MOA & Indications

A
  • Dopamine releasing agent
    • Antiviral drug that causes dopamine release in the striatum
  • May also act glutamate receptors
  • Used to control L-DOPA induced dyskinesias
    • Benefit may be transient
25
Q

Amantadine (Symmetrel)

Adverse Effects / Contraindications

A
  • Adverse CNS effects including restlessness, agitation, hallucination
  • Livedo reticularis (peripheral vascular condition-reddish blue skin)
  • Peripheral edema
  • Avoid use in patients who are prone to seizure and who have congestive heart failure
26
Q

Anticholinergics

MOA & Indications

A
  • Benztropine (Cogentin) or Trihexyphenidyl (Artane)
    • Several drugs in this class
    • If there is no response to one drug, switch to another
  • Restores the dopamine and cholinergic balance within the striatum
  • Indications
    • Improves rigidity/tremor
    • Only a minor effect on bradykinesia
27
Q

Anticholinergics

Adverse Effects / Contraindications

A
  • CNS effects such as restlessness, hallucination, confusion
  • May be additive with other drugs that have anti-muscarinic properties
  • Avoid use in prostatic hypertrophy, obstructive gastrointestinal disease, and glaucoma
28
Q

Catechol-O-Methyltransferase (COMT) Inhibitors

MOA & Indications

A

Tolcapone (Tasmar) and Entacapone (Comtan)

  • MOA:
    • ⊗ COMT which converts DOPA → 3-O-methyldopa and dopamine → 3-methoxytyramine
    • These agents enhance delivery of L-DOPA to the brain and stabilize dopamine
  • Indications:
    • ↑ Duration of effect of each L-DOPA dose, without ↑ the peak level of DOPA
    • Never used alone
    • They may be beneficial in treating ‘wearing-off” phenomena
29
Q

COMT Inhibitors

Adverse Effects

A
  • May need to reduce the level of L-DOPA in order to minimize dyskinesias and other dopamine related side effects
  • Tolcapone causes hepatotoxicity
    • Monitor liver function
  • Not a first line agent
30
Q

Stalevo

A
  • Combo tablet: carbidopa, levodopa, entacapone
  • For pts who experience end-of-dose “wearing off”
  • Entacapone extends the time levodopa is active in the brain (up to 10% longer)
31
Q

Limitations of Treatment

A
  • Treatment is symptomatic; it will not stop neuronal degeneration
  • “On-off effect”
    • Shortly after a dose, the patient will revert to Parkinson-like sx
    • Likely due to pre and postsynaptic changes
  • Off period can sometimes be related to decreasing plasma levels
    • Smaller more frequent dosing / time release preparation may help
  • Duration of benefit for Sinemet is 3 to 8 years
    • At this time, you can give a direct acting dopamine agonist
    • It acts directly; therefore, it does not need the presynaptic neuron
    • Dopamine agonists are also used in patients that cannot tolerate L-dopa
      • They can be used in combo with Sinemet
    • Side effects of dopamine agonists are similar to L-dopa
32
Q

Parkinson’s Treatment

Summary

A
  • Begin treatment when symptoms appear, early treatment decreases mortality
  • Keep doses low to minimize side effects
  • For mild symptoms ⇒ anticholinergic or amantadine
  • Long-term Maintenance Therapy
    • L-DOPA/Carbidopa
    • DA agonists
    • Selegiline (adjunct)
    • COMT inhibitors (adjunct)
    • Amantadine, anticholinergics (adjunct)

5. HDS Neuro Psych (46 decks)

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