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Neuro B4 - WLB > Basal Ganglia Pharmacology - Slattery > Flashcards

Basal Ganglia Pharmacology - Slattery Flashcards

1
Q

What is the pathologic basis of Parkinson’s disease?

A

Progressive loss of dopaminergic neurons in substantia nigra pars compacta.

(causes decreased released of Dopamine)

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2
Q

What is thought to cause the progressive loss of neurons in Parkinson’s Disease?

A
  • Impaired degradation of proteins
  • Oxidative stress
  • Mitochondrial damage
  • Genetic abnormalities (10-15%)
  • Etc.
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3
Q

What are common symptoms of Parkinson’s Disease?

A
  • Bradykinesia (slowness of movement)
  • Muscle rigidity
  • Resting tremor
  • Impaired postural balance
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4
Q

What are dyskinesias?

A

Abnormal involuntary movements.

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5
Q

What is the plasma half-life of Levodopa? Why?

A

Short plasma half-life

  • absorbed erratically from GI
  • amino acids can compete for transport
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6
Q

How is “replacement therapy” a means of treating Parkinson’s Disease?

A
  • Drugs aimed at restoring dopaminergic activity
    • less dopaminergic activity in striatum with Parkinson’s
      • increase by supplementing with exogenous dopamine precursor
      • target dopamine transporter
      • interact with dopamine receptor
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7
Q

What are the 6 drugs used for “replacement therapy” discussed in class?

A
  • Levodopa (prodrug/precursor)
  • Carbidopa (inhibits precursor activation (AAAD) in periphery)
  • Levodopa + Carbidopa = Sinemet
  • Entacapone (COMT inhibitors -** **inhibits precursor activation in periphery)
  • Selegiline (MAOIs - metabolizes dopamine)
  • Pramipexole (Dopamine receptor antagonists - target indirect pathway)
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8
Q

What is the MOA of Levodopa?

A
  • Transported across BBB by amino acid transporter
  • Enzymatically converted by L-aromatic amino acid decarboxylase (AAAD or Dopa Decarboxylase)
    • ideally converted once in brain, but also can happen in GI tract
  • Restores dopaminergic activity in striatum.
    • Activation of D1 receptors
      • Activates direct - facilitates voluntary movement
    • Activation of D2 receptors
      • Inhibits indirect - allows voluntary movement
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9
Q

What are the 3 main central adverse effects of Levodopa?

A
  • “Peak dose” or “On” period dyskinesia
    • activate motor system too much
  • Diphasic dyskinesia
    • symptoms at onset/offset of plasma levels
  • “Off” period dystonia
    • fixed/painful postures when plasma levels are ALL the way off
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10
Q

What are the peripheral adverse side effects of Levodopa?

A
  • Orthostatic hypotension
  • Nausea & Vomiting
  • Anorexia
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11
Q

What are additional central adverse side effects of Levodopa?

A
  • “On-Off” Phenomenon
    • has effect, then no effect, rapid switching
  • “Wearing off” Phenomenon
    • drug effect taper b/t doses
  • Confusion, Anxiety, Agitation, Insomnia, Nightmares, Depression, Psychotic reactions, Schizophrenia-like Delusions, Hallucinations
    • high [dopamine] in CNS
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12
Q

What is the current standard or first-line treatment for Parkinson’s Disease?

A

Sinemet

(Levodopa + Carbidopa)

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13
Q

What is the MOA of Carbidopa?

A
  • Inhibits L-aromatic amino acid decarboxylase (AAAD)
  • Ultimately:
    • inhibits peripheral decarboxylation of L-DOPA
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14
Q

When should you use Levodopa?

A
  • Diagnosing problems
  • Early in Parkinson’s Disease therapy
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15
Q

In early stages of Parkinson’s Disease, where is L-Dopa stored?

A

Pre-synaptic dopaminergic terminals of striatum

  • released gradually
  • smooth peaks & troughs
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16
Q

What is the MOA of Entacapone?

A

Decrease peripheral metabolism of L-DOPA by inhibiting COMT

(COMT usually activated to breakdown L-DOPA when AAAD is inhibited)

17
Q

What is the MOA of Selegiline?

A

Inhibits Monoamine Oxidase-B (MAO-B) from metabolizing dopamine in presynaptic terminal

18
Q

What is the MOA of Pramipexole?

A
  • Dopamine receptor agonist (D3 agonist)
  • Directly activates inhibitory D2 receptors of the indirect pathway in the striatum
  • Activation of D2 receptors:
    • Inhibits direct pathway
    • Allows for voluntary movement
19
Q

What is the MOA of Trihexyphenidyl?

A
  • Muscarinic antagonist (anticholinergic)
  • Blocks muscarinic receptor activity
    • not able to get ACh
  • Interrupted Dopamine:ACh balance
    • loss of DA innervation of striatum leads to relative excess of ACh activity
20
Q

What is the MOA of Amantadine (Symmetrel)?

A
  • Antiviral drug
  • Mechanism unclear, but thought to:
    • NMDA receptor antagonist
    • Decrease release/reuptake of Dopamine
    • Antimuscarinic
21
Q

Compared to Huntington’s Disease, what is different in Parkinson’s Disease?

A
  • Hypokinetic Disorder
  • Direct pathway inhibited/Indirect pathway active
  • Thalamus = more inhibited
    • less motor activity
  • Bradykinesia (slowness of movement)
  • Akinesia (lack of movement)
22
Q

Compared to Parkinson’s Disease, what is different in Huntington’s Disease?

A
  • Hyperkinetic Disorder
  • Direct pathway active/Indirect pathway inhibited
  • Thalamus = less inhibited
    • ​more motor activity
  • Diskinesias (uncontrolled movement)
  • Ballismus (violent flinging & flailing of limbs)
23
Q

What drug is becoming more common as a first-line therapy for Parkinson’s Disease, can help with “on-off” fluctuations with L-Dopa, and is also used to treat restless legs syndrome?

A

Pramipexole

(Dopamine receptor agonists)

24
Q

What drug is effective early in Parkinson’s disease as a monotherapy or combined with L-Dopa, smooths “on-off” fluctuations, reduces wearing off phenomenon, and may have a metabolite with neuroprotective effects?

A

Selegiline

(MAOIs)

25
Q

What drug is adjunctive with L-Dopa thereapy, has a smoother response, allows a more prolonged “on” time, and can be combined with L-Dopa alone or L-dopa & Carbidopa?

A

Entacapone

(COMT Inhibitor)

26
Q

What drug does not cross the BBB, only inhibits AAAD in the periphery, can reduce L-Dopa doses by 75%, and has few side effects than L-Dopa as a monotherapy?

A

Sinemet

(Levodopa + Carbidopa)

Neuro B4 - WLB (17 decks)

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