Parkinson's

Question 1

Parkison’s

S/S

Answer 1

• Bradykinesia/akinesia
• Tremor (pill-rolling)
• Rigidity (cogwheel)
• Impairment of postural balance

*mask face, shuffling gait, autonomic, weight-loss, anorexia, depression

Question 2

Parkinson’s

Pathology

Answer 2

• Dop neuron degeneration
• > 65 years
• more cells lost - worse disease

Question 3

Parkinson’s

CNS pathway

Answer 3

Nigrostriatal projection DEGENERATE

*substantia nigra –> Striatum

Question 4

Parkison’s

problem with replacing dopamine

Answer 4

Mesocorticolimbic = Ventral tegmental –> nucleus accumbens

Too much = psychosis

Question 5

Parkison’s

Smoking

Answer 5

Neuroprotective

Question 6

GABA pathway

Answer 6

Nigrostriatal = Dopamine (D2) inhibit GABA DIES

Cholinergic = Ach (M) excitatory

Question 7

MPTP

Answer 7

Goes to MPP+, selectively destroys Substantia Nigra neurons

Question 8

Selegiline

Answer 8

Stops development of parkinson in monkeys

Question 9

Suspected source of parkinson’s?

Answer 9

Pesticides, chemical in (country?)

Question 10

Pharm target =

Answer 10

Imbalance between striatal cholinergic + dopaminergic activity

Question 11

Pharm strategies

Answer 11

• Dopa replacement
• Enzyme inhibition
• MAO-B inhibition
• Up Dopa release, block reuptake
• stim dopa receptor
• anticholinergic (m)

Question 12

Dopamine replacement

Answer 12

• L-DOPA levodopa (dopa precursor)
• Use Aromatic amino acid transporter
• 95% lost in periphery

Dopa can’t cross

Question 13

Peripheral Dopa Toxicity

Answer 13

• Nausea (CTZ)
• Cardiac palpitations + arrythmia (b-agonist)
• Postural HypoTN (vascular DA receptor)

Question 14

DOPA

CNA toxicity

Answer 14

• Psychotic (accumbens, limbic system)
• Dyskinesias (striatum)
• On-off phenomenon (variable CNS metabolism)
  
  • -Off = dystonia
  • -ON = good but dyskenesia

Question 15

Control on -off phenomenon

Answer 15

Enzyme inhibition =
COMT
MAO-B

Question 16

L-DOPA

Contraindications

Answer 16

• Psychosis
• Melanoma
• Narrow angle glaucoma

look at slides for info

Question 17

L-Dopa

Rx interaction

Answer 17

• Non-selective MAO inhibitors - gets MAO-A (selective for MAO-B ok)
• Vitamin B6 (up peripheral metab=More S.E.)
• anti-psycs (work against each other)

Question 18

B6 effect on L-DOPA

Answer 18

Ups levodopa conversion to DA peripheral

Question 19

L- DOPA

Clinical problems

Answer 19

• Tolerance
• Gradually degenerating CNS nerves = can’t convert L-Dopa
• Limited effectiveness (1/3)

Question 20

L-DOPA best helps with these symptoms

Answer 20

Bradykinesia

Akinesia

Question 21

Use L-Dopa in beginning?

Answer 21

Physicians prefer to start later (tolerance)

Question 22

Cardidopa

Mech

Answer 22

Inhibits l-aad enzyme which converts L-dopa to peripheral Dopa = more goes in CNS

*COMT up (shunt) = inhibit too

Question 23

Inhibiting COMT

Answer 23

• Tolcapone - ALSO IN CNS (helps w/ ON OFF SYNDROME )

* Entacapone

Question 24

Enzyme inhibitors 
(cardidopa, -capone)

Advantages

Answer 24

• reduce L-dopa dose
• peripheral side effects reduces
• on-off reduced

Question 25

``` Enzyme inhibitors (cardidopa, -capone) ``` Disadvantages

Answer 25

CNS toxicity of L-dopa

Question 26

``` Enzyme inhibitors (cardidopa, -capone) ``` SIde effects

Answer 26

Due to up DA

Question 27

Rx preparations

Answer 27

* L-DOPA * Carbidopa * Sinemet (cardidopa + L-DOpA) COMT inhibitor * entacapone (no in CNS * tolcapone (liver toxicity)

Question 28

Nausea caused by

Answer 28

Peripheral Dopa ????

Question 29

How to inhibit MAO-B

Answer 29

Selegine | Rasagiline

Question 30

Inhibiting MAO Mech

Answer 30

MAO-B predominate form in striatum MAO-A = don't touch - need to handle catecholamines (avoid HTN)

Question 31

Selegiline

Answer 31

May reduce neurotoxic metabolite | *Eldepryl

Question 32

Nicotine

Answer 32

Neuroprotective + releases DA

Question 33

MAO-B S.E.

Answer 33

* UP CNS dopa effects * Oral selegiline causes amphetamine metabolism * no w/ non-selective MAO inhibitor

Question 34

Direct D2 stimulators

Answer 34

No dopamine releasing neuron * Ropinirole * Pramipexole * Bromocriptine

Question 35

Direct D2 stimulator On-off

Answer 35

NO ON-OFF Skipping neuron

Question 36

D2 ags Use

Answer 36

* L-dopa dose reduced * No on off * Refractory L-dopa patient * Used before L-dopa

Question 37

D2 agonist Contraindications

Answer 37

* Psychosis * recent MI, PV dz * peptic ulcer (N/V)

Question 38

Enhance DA release + inhibit reuptake

Answer 38

*Amantadine Need to have neurons to release dopa

Question 39

Amantadine Uses

Answer 39

* initial therapy * LESS bradykinesia, rigidity, tremor * L-dopa/cardidopa fluctuations/dyskinesias * NMDA receptors - improve cognition

Question 40

Amantadine S.E.

Answer 40

Mild | OD = toxic psychosis

Question 41

Antimuscarinics Rx

Answer 41

Benztropine | Trihexyphenidyl

Question 42

Antimuscarinic Uses

Answer 42

* combo w/ L-dopa * mild parkison's (tremor only) * better on tremor and rigidty than bradyinesia

Question 43

Antimuscarinics contraindications

Answer 43

* Prostatic hypertrophy * Obstructive GI disease * Narrow angle glaucoma

Question 44

Early non-pharm treatment

Answer 44

Lifestyle / exercise

Question 45

For Mild symptoms Tx/ initial tx

Answer 45

* MAO-B inhibtors * Amantadine * Anticholinergics Younger = D2 agonist

Question 46

for Moderate symptoms

Answer 46

Levodopa | D2 agonist

Question 47

Antimuscarinic S.E.

Answer 47

Peripheral = dry mouth, blurred vision, Blurred vision, mydriasis, urinary retention, nausea Central = Drowsiness, mental slowness, Inattention, Restlessness

Question 48

D2 agonist S.E

Answer 48

Peripheral = nausea (CTZ), hypoTN CNS = Dyskinesia (less than L-DOPA) Psychosis (more than L-DOPA)