Block 2: Neurodegenerative Disorders

Front 1

How many does Parkinson's affect?

Back 1

1% over 50

Front 2

Symptoms of Parkinson's

Back 2

akinesia
tremor
rigidity
alteration of posture, mask-like face, shuffling gait, loss of associative movment, and hypersalivation

Front 3

Most obvious early sign of Parkinson's?

Back 3

Tremor- usually pill-rolling

Front 4

How is the rigidity in PK's characterized?

Back 4

cogwheel

Front 5

How long w/o treatment before death?
With?

Back 5

9 years
20 years

Front 6

Which tissues in the brain are affected because of PK's?

Back 6

Striatal tissue (caudate and putamen) show 10% of normal dopamine

Front 7

What is the offending neurotransmitter in PK's?

Back 7

Dopamine

Front 8

Where is dopamine made? What does this area display in PK's?

Back 8

Pars compacta of the substantia nigra
Degeneration of the dopaminergic neurons

Front 9

How much degeneration do you need in PK's to show disfunction?

Back 9

≧70%

Front 10

What is the normal pathway of dopamine?

Back 10

Pars Compacta of Substantia Nigra -- release of DA -- D2 (inhibits cholinergic release Ach)and D2 (inhibits muscarinic release GABA to Globus Pallidus)

Front 11

What's the affect of decreased dopamine on the pathway? How should we treat the defect?

Back 11

Decreased D2 inhibition, increased release of Ach.

Replace dopamine and block Ach

Front 12

Can we give exogenous dopamine for treatment of PK's?

Back 12

No, doesn't cross BBB, give L-dopa which does.

Front 13

How much L-dopa do we give? Why?

Back 13

Large doses, more than 95% ingested is decarboxylated in peripheral tissues.

Front 14

Why give l-dopa gradually? What does L-dopa do?

Back 14

Reduce side effects and toxicity
Reduces bradykinesia and rigidity, less effective in reducing tremor.

Front 15

What are the side effects of L-dopa?

Back 15

Nausea- stimulation of DA receptors in area postrema of medulla.

Orthostatic hypotension- presynaptic DAr inhibit NE release that would normally constrict vessels.

Cardiac arrhythmias- DA stim of Beta receptors

Psychotic-like symptoms- Activate DAr in mesolimbic system.

Front 16

Long term complications of L-dopa

Back 16

abnormal involuntary movements, faciolingual tics, bobbing,and rocking movements. *decreased affectiveness of l-dopa leading to on-off phenomenon

Front 17

What is the on-off phenomenon?

Back 17

Partial l-dopa resistance due to pronlonged treatment leads to asymptomatic followed by severe symptom cycles.

Front 18

Contraindication of L-dopa

Back 18

Never with MAOI- would result in massive increase of sympathomimetic amines leading to hypertensive crisis.

Antipsychotic drugs (pnenothiazine or butyrophenone) antagonize l-dopa.

Front 19

Why do you combine Carbidopa with L-dopa?

Back 19

Carbidopa is a peripheral L-aromatic Decarboxylase inhibitor. Coadministration allows lower doses of L-dopa to be given and still get to the brain.

Front 20

Why combine L-dopa with Selegiline?

Back 20

This is a MAO B inhibitor. It decreases dopamine breakdown in the brain, but does not cause catecolamine build-up in the peripheral tissues (no HTN crisis).

Front 21

When given with carbidopa, how much l-dopa should be give to reach the TE?

Back 21

75% less than w/o carbidopa

Front 22

Is the on-off phenomenon avoided by combination with carbidopa?

Back 22

No, may even be worse.

Front 23

Sinemet

Back 23

1 part carbidopa to 10 parts l-dopa, most widely used med for Parkinson's

Front 24

Selegiline (Deprenyl)
(se le' ji leen)

Back 24

MAO B inhibitor, predomintates in the brain

Front 25

What does selegiline do? What are it's advantages?

Back 25

decrease breakdown of dopamine in brain, but don't cause catecholamine build up in peripheral tissues, therefore no HTN crisis

Front 26

Bromocriptine, Pergolide

Back 26

Dopamine agonists

Front 27

Ropinirol
Pramipexole

Back 27

Dopamine agonists

Front 28

Side effects of agonists

Back 28

Nausea, hypotension, dyskinesia, hallucinations, and delusions

Front 29

Why combine bromocriptine with l-dopa?

Back 29

Reduce on-off phenomenon

Front 30

Why are side effects such as emesis and hypotension a problem w/dopamine agonists?

Back 30

They activate peripheral dopamine receptors

Front 31

How can we avoid agonist side effects?

Back 31

Achieve a higher T.I. by combining with a dopaminergic antagonist

Front 32

Centrally acting anticholinergics (CAA)

Back 32

Benztropine
Trihexyphenidyl

Front 33

Why use CAAs? Side effects?

Back 33

Reduce tremor
dry mouth, blurred vision, urinary retension

Front 34

Amantidine

Back 34

Antiviral drug found to improve Parkinson symptoms.
Releases endogenous DA

Front 35

COMT inhibitors

Back 35

Tolcapone* may cause liver damage
Entacapone
Prevent the breakdown of l-dopa

Front 36

Recommendations for early stage Parkinson's

Back 36

Dopamine agonists (pramipexole or ropinirole)

Front 37

Recommendations when DA agonists no longer work

Back 37

Add l-dopa and carbidopa
Can add COMT inhibitors (entacapone) to reduce wearing off periods

Front 38

What are the low dose atypical antipsychotics? Why use them?

Back 38

Risperidone, Olanzapine, Quetiapine
Control hallucinations caused by l-dopa

Front 39

Why use selegiline in newly diagnosed patient?

Back 39

May delay the onset of symptoms

Front 40

Dopamine precursors
Replenishes dompamine in striatum

Back 40

l-dopa

Front 41

Side effects of l-dopa

Back 41

nausea, orthostatic hypotension, arrhythmias, hallucinations, delusions, dyskinesias

Front 42

peripheral l-aromatic decarboxylase inhibitor (does not enter brain)

Back 42

Carbidopa

Front 43

MA of Carbidopa

Back 43

prevents conversion of l-dopa to dopamine in peripheral tissues

Front 44

Side effects of Carbidopa

Back 44

None

Front 45

MAO B inhibitor

Back 45

Selegiline

Front 46

MA of Selegiline, side effects

Back 46

Prevents oxidation of dopamine in brain
May cause HTN at high dose

Front 47

Dopamine agonists

Back 47

Bromocriptine/Pergolide

Front 48

Effect of DA agonists

Back 48

Stimulate DP receptors in striatum. Reduce on-off

Front 49

Side effects of DA agonists

Back 49

Nausea, Ortho hypotension, hallucinations, delusions, dyskinesias

Front 50

Somewhat selective D2,D3 DA receptor agonists

Back 50

Ropinirole/Pramipexole

Front 51

Muscarinic cholinergic receptor antagonists

Back 51

Benztropine
Trihexyphenidyl

Front 52

MA for MS cholinergic receptor antagonists

Back 52

Block muscarinic receptors in striatum- useful only very early in dz

Front 53

Side effects of MSCR antagonists

Back 53

Dry mouth, blurry vision, urinary retention

Front 54

Indirectly causes the release of endogenous DA
Side effects?

Back 54

Amantidine
Hallucinations

Front 55

COMT inhibitors

Back 55

Tolcapone
Entacopone

Front 56

MA of COMT inhibitors

Back 56

prevent breakdown of l-dopa by COMT

Front 57

Most common form of dementia

Back 57

Alzheimer's- progressive impairment of memory and cognitive fxn.

Front 58

Pathology of Alzheimer's

Back 58

Brain accumulation of plaques and tangles composed of Beta amyloid

Front 59

Four drugs used to treat Alzheimer's. All are...?

Back 59

Tacrine
Donepezil
Rivastigimine
Galantamine
All ACEi

Front 60

Difference between Tacrine and donepezil, rivastigmine, and galantamine?

Back 60

Tacrine is non-selective, the others are brain-selective

Front 61

Adverse effects of Alzheimer drugs

Back 61

Nausea, vomiting, diarrhea, abdominal pain, anorexia
*Tacrine has hepatic toxicity

Front 62

Memantine

Back 62

NMDA receptor antagonist may have neuroprotective properties may slow progression of Alzheimer's

Front 63

Other drugs being considered for Alzheimer's

Back 63

NSAIDS, estrogen, nicotine, statins

Front 64

L-dopa, carbidopa, Sinemet, bromocriptine, ropinirole, pramipexole, amantadine, selegiline, propranolol, benztropine, trihexyphenidyl, entacapone

Back 64

Parkinson's

Front 65

Tacrine, donepezil, rivastigmine, galantamime, memantine

Back 65

Alzheimer's