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Flashcards in Parkinson's Disease Deck (58)
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1

Which part of the brain is affected by Parkinson's Diease?

_________

Which neurotransmitters are involved in Parkinson's Disease?

Nigrostriatal Projection

_______

  1. Dopamine
  2. Acetylcholine
  3. GABA

2

What is often the earliest sign of Parkinson's disease?

Tremor (Pill Rolling)

3

What type of Rigidity is expressed in Parkinson's Disease?

Cogwheel type; increased muscle tone

________

Definition:

  • When a limb is bent, it seems to catch at regular points throughout its range of motion, much as a second hand jerks from interval to interval instead of smoothly traversing the face of a clock.
  • muscular rigidity in which passive movement of the limbs (as during a physical examination) elicits ratchet-like start-and stop movements through the range of motion of a joint

4

What symptoms make up the clinical syndrome of Parkinson's disease?

  1. Bradykinesia/akinesia
  2. Tremor ("pill rolling")
  3. Rigidity ("Cogwheel type")
  4. Impairment of postural balance (shuffling gait; disturbances in gait; falling)

5

What are the autonomic symptoms of Parkinson's disease?

  1. sweating
  2. constipation
  3. hypersalivation
  4. urinary retention

6

What is the total symptom profile of Parkinson's Disease?

Clinical Syndrome

  1. Bradykinesia/akinesia
  2. Tremor ("pill rolling")
  3. Rigidity ("Cogwheel type")
  4. Impairment of postural balance (shuffling gait;disturbances in gait; falling)

Autonomic symptoms

  1. sweating
  2. constipation
  3. hypersalivation
  4. urinary retention

Other symptoms

  1. mask-like face
  2. weight loss
  3. anorexia
  4. depression

7

What does the clinical severity of Parkinson's Disease correspond to?

Loss of dopamine neurons in the substantia nigra pars compacta

8

Approximately what level of cell loss of the dopamine neurons in substantia nigra pars compacta results in symptoms?

Symptoms appear after >50% cell loss

9

Which age group is most common for Parkinson's Disease?

Age 65 and older

10

What is the basic pathology of Parkinson's Disease?

  • Progressive degeneration of dopamine neurons in substantia nigra pars compacta
  • Disease is progressive, ultimately fatal

11

What is a significant comorbidity with Parkinson's Disease?

depression

12

Describe, in detail, the pathophysiology of Parkinson's Disease in the Nigrostriatal Projection?

Nigrostriatal Projection

  • Nigrostriatal Neuron and Cholinergic Interneuron act on striatal GABAergic efferent neuron
  • DA from nigrostriatal neuron is inhibitory; ACh from cholinergic interneuron is excitatory
  • Nigrostriatal neurons die, thus they do not produce DA and Cholinergic interneuron does not die; thus balance is altered toward ACh excitatory

13

What are the 6 Pharmacological strategies for treating Parkinson's Disease?

  1. DA replacement (L-DOPA)
  2. Enzyme inhibitors to enhance CNS delivery
  3. MAO-B inhibition to prolong CNS effects
  4. Enhance DA release, block re-uptake
  5. Directly stimulate DA receptors
  6. Anticholinergics (antimuscarinics)

14

Broadly speaking, what does Pharmacotherapy for Parkinson's Disease aim to accomplish?

Treat the imabalance between striatal cholinergic and dopaminergic activity

15

You are seeking to treat Parkinson's Disease using the pharmacological strategy of DA replacement. What do you use? How does it work?

L-DOPA; L-DOPA is a precursor for DA synthesis

16

What is the fate of orally administered L-DOPA?

~70% metabolism in GI tract

~27-29% Peripheral Tissues (toxicity)

1-3% Brain

17

What is L-DOPA utilized instead of DA?

L-DOPA is able to traverse the blood/brain barrier; DA is not able to

18

How much of L-DOPA is decarboxylated in the periphery? What side effects does this lead to?

~95% of L-DOPA is decarboxylated in the periphery

Peripheral Side Effects

  1. Nausea
  2. Cardiac palpitations and arrythmias
  3. Postural hypotension

19

What are the CNS toxicities and side effects of L-DOPA?

  1. Psychotic symptoms
  2. Dyskinesias
  3. On-Off Phenomenon

20

The motor CNS toxicities of L-DOPA are due to what? Where?

Motor effects due to increased DA in the striatum

21

The psychotic CNS toxicities of L-DOPA are due to what? Where?

Psychotic effects due to increased DA in the accumbens

22

What causes on-off phenomenon? Describe the "on" phase? Describe the "off" phase? Which enzymes, if inhibited, reduce on-off phenomenon?

Cause: Variable CNS metabolism of DA by COMT and MAO-B

______

On-phase: PD symptoms are controlled (but dyskinesias)

_____

Off-phase: PD symptoms are not controlled (may have dystonias/sustained muscle contractions)

______

If COMT and MAO-B are inhibited, on-off phenomenon is reduced

23

3 contraindications of L-DOPA

  1. Psychosis (already have too much DA activity)
  2. Melanoma (L-DOPA is precursor for melanin in skin)
  3. Narrow angle glaucoma (due to alpha1 agonist activity at high concentrations of DA which causes an inability of vitreous humor to drain from canal of Schlemm)

24

Name 3 interactions with other drugs of L-DOPA

  1. Nonselective MAO inhibitors (antidepressants)
    • risk of hypertensive crisis (alpha a1 agonism)
    • Exception: Selegeline
  2. Pyridoxine (Vitamin B6)
    • Enhances peripheral metabolism of L-DOPA via L-AAD (more peripheral side effects)
  3. Anti-psychotics
    • Will block effects at DA receptors

25

How long after prescription is L-DOPA most effective for a Parkinson's Patient? What happens longer term?

Most effective first 3-4 years of use. Longer term:

  • Increasing intolerance to side effects (result in need to decrease dose)
  • Decreased effectiveness as more neurons die and thus, less neurons to convert L-DOPA to DA

26

What is L-DOPA's effectiveness?

  • Effective 1/3 pts
  • Somewhat effective 1/3 pts
  • Ineffective 1/3 pts

27

L-DOPA is particularly good at treating which PD symptoms?

  • Bradykinesia
  • Akinesia

28

In a younger Parkinson patient, would you recommend L-DOPA as first line therapy?

No; most physicians prefer to start young PD patients with something other than L-DOPA

29

If you would like to treat Parkinson's Disease by employing the strategy of inhibiting the enzyme L-AAD in the periphery to increase delivery of the DA precursor and slow metabolism of CNS DA, what pharmacological agent would you use?

Carbidopa

30

What is the mechanism of action of carbidopa?

  • Inhibit L-AAD in the periphery
  • BUT; this causes a shunt to an alternate metabolic pathway such that COMT upregulates in the periphery

___________

In order to inhibit COMT use tolcapone or entacapone