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Neuro Block 4 - KJ > Basal Ganglia Pharmacology > Flashcards

Basal Ganglia Pharmacology Flashcards

1
Q

What is the function of the direct pathway?

A

-Allows for/releases a selected movement from suppression

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2
Q

What is the function of the indirect pathway?

A

-Suppresses competing, non-selected movements

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3
Q

Describe the Direct Pathway:

A
  1. Striatum receives excitatory glutaminergic input from cortex
  2. Striatum sends inhibitory GABA signal to internal globus pallidus
  3. Internal globus plaids now produces less of its own neurotransmitter (GABA)
  4. Less GABA reaches the thalamus (less inhibition)
  5. Increased excitatory outflow from thalamus to cortex
  6. Selected/desired motor activity increases
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4
Q

Describe the Indirect Pathway:

A
  1. Striatum receives excitatory glutaminergic input from cortex
  2. Striatum sends inhibitory GABA signal to external globus pallidus
  3. External globes pallidus now produces less of its own NT (GABA)
  4. Less GABA reaches the sub thalamic nucleus (less inhibition)
  5. Subthalamic nucleus now produces more of its own NT (glutamate)
  6. More excitatory glucatmate reaches internal globus pallidus
  7. Internal globus plaids now produces more of its own NT (GABA)
  8. More GABA reaches the thalamus (inhibition)
  9. Reduced excitatory outflow from thalamus to cerebral cortex
  10. Competing motor activity decreases
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5
Q

What innervates the striatum?

A

Dopaminergic neurons fo substantia nigra pars compacta

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6
Q

Some striatal neurons express D1 and some express D2. What pathway expresses D1 and which D2?

A

D1 - direct pathway

D2 - indirect pathway

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7
Q

What does dopamine do the in striatum?

A

Activates direct (D1) pathway and inhibits indirect (D2) pathway.

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8
Q

What does the coordinated action of the Basal Ganglia circuit (direct and indirect pathways) do?

A

-Circuit to signal start and stop action sequences

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9
Q

Describe hypokinetic disorders:

A
  • Direct pathway inhibited/indirect pathway active
  • Thalamus = more inhibited, LESS motor activity
  • Results in bradykinesia (slowness of movement) or akinesia (lack of movement)
  • PARKINSON’S DISEASE
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10
Q

Describe hyperkinetic disorders:

A
  • Indirect pathway inhibited/Direct pathway activated
  • Thalamus = less inhibited, MORE motor activity
  • Results in dyskinesias (uncontrolled movement), such as ballismus (violent flinging limbs)
  • HUNTINGTON’S DISEASE
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11
Q

What does a dopaminergic neuron do?

A

Releases dopamine!

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12
Q

What is the pathogenesis of Parkinson’s disease?

A
  • Progressive loss of dopaminergic neurons in the substantial nigra pars compacta
  • Less DA in striatum:
  • –Decreased direct pathway activity
  • –Increased indirect pathway activity
  • –Lose coordination of direct/indirect activity
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13
Q

What happens in the thalamus and motor cortex in Parkinson’s disease?

A
  • Marked INCREASE in INHIBITION of thalamus

- REDUCED EXCITATION of motor cortex

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14
Q

What is thought to cause Parkinson’s disease?

A
  • Genetic component (10-15%) of cases with recognized genetic abnormalities
  • Impaired degradation of proteins, oxidative stress, mitochondrial damage, etc. (causes cell death of dopaminergic neurons)
  • End result is neuronal cell death (specific subset of neurons)
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15
Q

What are the common symptoms of Parkinson’s disease?

A
  • Bradykinesia - slowness of movement
  • Akinesia (no movement)
  • Muscle rigidity
  • Resting tremor
  • Impaired postural balance
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16
Q

What do current therapies for Parkinson’s do?

A

Treat symptoms only. They are mostly aimed at restoring dopaminergic activity.

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17
Q

Does dopamine cross the BBB?

A

No

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18
Q

Why do we give L-DOPA (prodrug of dopamine) instead of dopamine?

A

Levodopa can cross the BBB while dopamine does not.

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19
Q

What transports Levodopa across the BBB?

A

Amino Acid Transporter

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20
Q

What converted LDOPA into dopamine?

A

L-aromatic amino acid decarboxylase (AAAD) [dopa-decarboxylase] enzymatically converts LDOPA to DA

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21
Q

How is Levodopa administered?

A

Orally effective

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22
Q

What problem is encountered when Levodopa is administered alone?

A

Significant AAAD decarboxylase activity in GI tract!

  • Significant conversion to dopamine in periphery, dopamine can’t cross BBB
  • Ultimately <5% of L-DOPA enters CNS
  • Peripheral dopamine causes side effects
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23
Q

What side effects does peripheral dopamine cause?

A

-Nausea, orthostatic hypotension

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24
Q

Why do you give carbidopa with levodopa?

A

It inhibits peripheral breakdown of levodopa.

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25
Q

What is Levodopa + Carbidopa called? What is this combo?

A

Sinemet

-Current standard treatment for PD

26
Q

What is the mechanism of carbidopa?

A

It inhibits L-aromatic amino acid decarboxylase (AAAD)
-Does not cross BBB, only inhibits AAAD in periphery
[Inhibits peripheral decarboxylation of L-DOPA]
-Can reduce L-DOPA dose by 75%
-Fewer side effects!

27
Q

What is Levodopa’s mechanism of action?

A
  • All effects due to metabolism to dopamine
  • Restores dopaminergic activity to striatum
  • Activates D1 receptors (activates direct pathway - facilitates voluntary movement)
  • Activates D2 receptors (inhibits indirect pathway - allows voluntary movement)
28
Q

What effect does Levodopa have?

A
  1. Decreases akinesia, rigidity, and tremor
    (no effect in patients with other neurological diseases)
  2. Most effective early in therapy (80% marked improvement, 20% virtually normal motor function)
  3. Less effective over time
    (progressive loss of dopaminergic neurons - without dopaminergic neurons you can’t utilize the levodopa - enzymes that convert levodopa to dopamine dies with the cells/disappear)
29
Q

What are the pharmacological properties of levodopa?

A
  1. Short plasma half-life, absorbed erratically from GI
    - Amino acids can compete for transport (GI –> blood, blood –> brain)
    - Peaks and troughs in plasma and brain levels
  2. Early stages of PD, L-DOPA stored in presynaptic dopaminergic terminals of striatum and released gradually
    - Smooth peaks and troughs
  3. As dopaminergic neurons are lost, L-DOPA’s effect becomes shorter and begins to mirror plasma levels
    - Pulsatile plasma L-DOPA levels, pulsatile effects
    - Can lead to dyskinesia
30
Q

What are the four adverse effects of Levodopa pharmacology?

A
  1. Dyskinesias - abnormal involuntary movements
  2. “Peak dose” or “on” period dyskinesia
  3. Diphasic dyskinesia
  4. “Off” period dystonia
31
Q

What is the “Peak dose” or “on” period dyskinesia?

A

Adverse effect of Levodopa

  • High plasma levels of levodopa, in parallel with maximal antiparkinsonian benefit
  • Brief, abrupt, irregular, unpredictable movements (chorea)
  • Predominantly involve neck, trunk, and upper limb
32
Q

What is diphasic dyskinesia?

A

Adverse effect of Levodopa

  • Appears at the onset and offset of the levodopa effect, coinciding with rising and falling plasma levodopa levels
  • Often repetitive, slow movements of lower limbs, often coinciding with tremor in the upper limbs
33
Q

What is “Off” period dystonia?

A
  • Fixed and painful postures more frequently affecting the feet, but which can be segmental or generalized in distribution
  • Happens when levels fall all of the way off
  • Constant flexing, fixed, painful postures
34
Q

What is the “On-Off” phenomenon?

A
  • Sudden and rapid loss of clinical effect

- –Can last 30 minutes to 4 hours, occur up to 10 times/day

35
Q

What is the “wearing off” phenomenon?

A
  • Drug effect “wears off” between doses, symptoms fluctuate
  • Dramatic initial effect, but drug becomes less effective over time
  • Options: increase dose, decrease dosing interval, add COMPT inhibitor!!
36
Q

Where do we find dopamine receptors/where could levodopa potentially go?

A
  • CNS - limbic system and frontal cortex (schizophrenia), other areas
  • Brainstem - chemoreceptor trigger zone, outside of BBB
  • Pulmonary artery
  • Kidneys
37
Q

What are adverse effects of levodopa in CNS?

A

Confusion, anxiety, agitation, insomnia, nightmares, depression

  • Psychotic reactions - schizophrenia-like delusions and hallucinations
  • –Due to high conc. of dopamine in CNS
  • –Reversible with decreased dosage
38
Q

What effects are related to peripheral dopamine (levodopa)?

A
  1. Orthostatic hypotension

2. Nausea, vomiting, anorexia (peripheral stimulation of chemoreceptor trigger zone)

39
Q

What is COMT?

A

Another enzyme that can break down L-DOPA

40
Q

What do COMT inhibitors do?

A

Decrease peripheral metabolism of L-DOPA by COMT (catechol-O-methyltransferase)

  • Inhibition of AAAD (carbidopa treatment) is associated with compensatory activation of COMT
  • Giving COMT inhibitor is adjunctive to L-DOPA therapy - you can reduce the L-DOPA dose
41
Q

What can a COMT inhibitor cause in response?

A

Smoother response to drug, more prolonged “on” time.

-There are adverse effects related to increased plasma L-DOPA

42
Q

What is Entacapone?

A

COMT Inhibitor

  • Can be combined with L-DOPA alone or L-DOPA and Carbidopa (Stalevo)
  • Stalevo associated with increased freq. of dyskinesia
43
Q

What is Huntington’s Disease neurological symptoms?

A
  • Associated with psychiatric and cognitive issues

- Neuronal degeneration eventually causes death within 10 to 20 years

44
Q

What are the genetics of Huntington’s Disease?

A
  • Hereditary Hyperkinetic disorder
  • –Expanded CAG (polyglutamine) repeats in the huntington gene [>40 repeats = affected, full penetrance]
  • –Autosomal dominant
  • –Neuronal deregulation eventually causes death within 10 to 20 years
  • –Genetic test is available
  • –No cure (no neuroprotective therapy)
  • –All treatments attack symptoms = attempt to decrease excitatory activity of direct pathway
45
Q

What is Chorea?

A

Symptom of Huntington’s Disease

-Brief, abrupt, irregular, unpredictable, non-stereotyped movements

46
Q

What is MAO-B?

A

Metabolizer (primary) of dopamine, useful for PD treatment target

47
Q

What are monoamine oxidase inhibitors (MAOIs)?

A
  • Block MAO-B
  • Effective early in PD as mono therapy or combined with L-DOPA
  • Lower dose of L-DOPA needed then
  • Smooths “on-off” fluctuations, reduce wearing off phenomenon
48
Q

What is an example of a MAOI?

A

Selegiline

-May also have neuroprotective effect

49
Q

What do dopamine receptor agonists do?

A
  • Direct action on receptors
  • All examples in D2 family (D2, D3 & D4)
  • Bypasses conversion of L-DOPA to dopamine
50
Q

Where is AAAD most active?

A

Dopaminergic neurons!

51
Q

When dopaminergic neurons are lost. . .

A

Synthesis of dopamine from L-DOPA is compromised!

52
Q

What is becoming more active as first line therapy?

A

Dopamine receptor antagonists:

-They have less adverse effects (response fluctuations, dyskinesia) than L-DOPA therapy

53
Q

What other effects can Dopamine receptor agonists have?

A
  • Can help with “on-off” fluctuations with L-DOPA

- Also used to treat restless leg syndrome

54
Q

What is the D3 agonist?

A

Pramipexole

55
Q

What is the D2 agonist?

A

Ropinirole

56
Q

What is the muscarinic antagonists (anticholinergics) that used to be used as Parkinson’s treatment for 100 years?

A

Trihexyphenidyl

57
Q

What is known about Trihexyphenidyl’s mechanism?

A
  • ACh used as NT by a small group of stratal interneurons

- Biological basis unclear: DA-ACh balance: loss of DA innervation of striatum leads to relative excess of ACh activity

58
Q

What are side effects of Trihexyphenidyl?

A

Sedation, mental confusion, constipation, urinary retention

59
Q

What is the opposite disease to parkinson’s?

A

Huntington’s

60
Q

What are alternative Parkinson’s treatments?

A

-Tissue transplantation
(human fetal adrenal medullary tissue into caudate nucleus)
-Electrical stimulation (Deep brain stimulation)
-Surgery
—Pallidotomy- alleviates akinesia, rigidity, and drug induced dyskinesia
—Thalamotomy - ameliorates tremor

61
Q

What (neurologically) causes Huntington’s disease?

A

Associated with basal ganglia degeneration.

  • Dec. in activity of basal ganglia’s mitochondrial pathway
  • Degeneration of striatal neurons projecting to external globus pallidus leads to:
  • –Inc. external globus pallidus activity (GABA)
  • –Dec. subthalamic nucleus activity (glutamate)
  • –Dec. Internal globus plaids activity (GABA)
  • –Loss of thalamic inhibition
  • –Increased thalamic excitatory drive!/Involuntary movement
62
Q

What pathway is affected in Huntington’s disease?

A

Decreased activity in indirect pathway!

Neuro Block 4 - KJ (12 decks)

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