Parkinson's Disease

Question 1

Parkinson’s Disease

• Reduced dopamine
• Goals: restore dopamine receptor function; inhibition of muscarinic cholinergic receptor
• No curative treatment

Answer 1

Levodopa
Dopamine receptor agonist
MAOIs
Catechol-O-Methyltransferase (COMT) inhibitors
Muscarinic cholinergic receptor antagonist
Amantadine

Question 2

Levodopa

- First line for Parkinson’s

Answer 2

• Prodrug (immediate metabolic precursor of dopamine, Levodopa crosses BBB while dopamine can’t)
• MOA: restoration of synaptic concentration of dopamine; activation of post-synaptic D2 receptors (indirect pathway) and D1 receptors (direct pathway)
• ADR: Dyskinesias (80% of long term use, Choreiform movements, dose related, more in young pt); “ON (improved mobility, marked dyskinesia)- OFF (marked akinesia)” effect (fluctuation in clinical response to levodopa, fixed when taken with dopamine receptor agonist)
• ACUTE ADR (related to increased peripheral [dopamine]: NAUSEA/anorexia (treat with peripherally acting dopamine antagonist)/hypotension
• OTHER ADR: confusion, insomina, nightmares, schizophrenic-like syndrome (delusions and hallucinations)
• CONTRAINDICATIONS: non selective MAOI (d/c >2weeks before starting levodopa); h/o malignant melanoma; narrow angle glaucoma
• Monitor LFTs
• Best results obtained in first few yrs of treatment

Question 3

Carbidopa

Answer 3

• Inhibits dopa decarboxylase
• Prevents peripheral conversion of levodopa to dopamine (allows levodopa to cross BBB)
• Increases bioavailability

Question 4

Dopamine Receptor Agonist

Answer 4

• ADR: anorexia, N/V, hypotension, cardiac arrhythmias, headache, confusion, hallucinations, sedation, pulmonary fibrosis
• Lower incidence of response fluctuation and dyskinesia than long term levodopa
• Use before levodopa or w/ low dose of carbidopa/levodopa

Question 5

Ergot Dopamine Receptor Agnoist

Answer 5

Bromocriptine (Parlodel)

Cabergoline (Dostinex)

Question 6

Bromocriptine (Parlodel)

Answer 6

• MOA: Selective D2 receptor agnoist

Question 7

Carbergoline (Dostinex)

Answer 7

• MOA: Selective D2 receptor agonist
• Longer acting than bromocriptine
• associated with cardiac valvulopathy when used at parkinson’s dosing

Question 8

NonErgot Dopamine Receptor Agonists

Answer 8

Pramipexole (Mirapex)
Ropinirole (Requip)
Rotigotine (Neupro)
Apomorphine

Question 9

Pramipexole (Mirapex)

- Advanced Parkinson’s dz

Answer 9

• MOA: D3 receptor (also D2/D4)
• USE: restless legs syndrome
• Possibly neuroprotective- scavenges H2O2

Question 10

Ropinirole (Requip)

Answer 10

• MOA: D2 receptor agnoist
• effective as monotherapy with mild dz
• USE: restless legs syndrome

Question 11

Rotigotine (Neupro)

Answer 11

• Transdermal patch
• Sudden somnolence (asleep for driving, eating, talking)
• NO driving!

Question 12

Apomorphine

Answer 12

• MOA: Potent D1/D2 agnoist
• SubQ injection
• USE: temp relief of “off” periods of akinesia
• ADR: dyskinesias, drowsiness, sweating, hypotension)
• short period of effectiveness

Question 13

What happens if you give metoclopramide to Parkinson’s pt?

Answer 13

Metoclopramide: dopamine agonist

- increase parkinson’s symptoms

Question 14

Monoamine Oxidase Inhibitors (MAOIs)

Answer 14

• MAO-A: primarily metabolizes NE and 5-HT

- MAO-B: primarily metabolizes dopamine

Question 15

MOA-A

Answer 15

Tyramine (soy sauce, beens, beer)…

Question 16

MAO-B

Answer 16

Selegiline
Rasagiline
- selective, irreversible inhibitors of MAO-B

Question 17

Selegiline

Answer 17

• MOA: MAO-B inhibitor
• USE: early Parkinson’s as monotherapy or in combination with levodopa; helps reduction in levodopa dose or may smooth the “on-off” fluctuations
• ADR: blocks MAO-A at high doses (hypertensive crisis due to peripheral accumulation of NE); fatal hyperthermia (conjunction with meperidine, cocaine, fluoxetine)

Question 18

Rasagiline (Azilect)

Answer 18

• Irreversible MAO-B inhibitor
• USE: early parkinson’s and adjunct with levodopa
• Extensive liver metabolism (CYP1A2)
• DRUG INTERACTIONS: meperidine, dextromethorphan, St. John’s wort, cyclobenzaprine, ciprogloxacin
• HEPATIC adjust

Question 19

Catechol-O-Methyltransferase (COMT) Inhibitors

Answer 19

• COMT: liver, kidney/ heart, lung, smooth and skeletal muscles
• Metabolizes catecholamines (dopamine, NE, EPI)
• Metabolizes Levodopa to 3-OMD in brain and periphery
• MAO and COMT both metabolize catecholamines: avoid non selective MAOIs with COMT (MAO-BI generally OK)
• Watch liver

Question 20

Tolcapone (TASMAR) and Entacapone (Comtan)

• INCREASE availability of Ldopa
• Adjunctive therapy with Levodpa

Answer 20

• Selective COMT inhibitors: diminish peripheral metabolism of levodopa
• USE: may reduce “on-off” flunctuations
• ADR: increase [Levodopa] (dyskinesias, N, confusion); D/abd pain, orthostatic hypotension, sleep disorders, orange urine discoloration
• Tolcapone ADR: POTENTIALLY HEPATOTOXIC
• Entacapone: P450 inhibitor at high doses
• Taper dosing for discontinuation

Question 21

Stalevo (levodopa/carbidopa/entacapone)

Answer 21

• Combination drug

Question 22

Amantadine (Symmetrel)

Answer 22

• Antiviral drug w/ anti-Parkinsonian properties
• MOA unclear; potentiates dopaminergic function (modifying synthesis, release, or reuptake of dopamine)
• USE: best in advanced PD w/ dyskinesias
• Less effective than levodopa/bromocriptine
• ADR: Primarily CNS (restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, confusion, seizures); HA, edema, postural hypotension, HF, GI disturbances
• Overdose= acute toxic psychosis
• RENAL adjust

Question 23

Anticholinergics

- Mediate cholinergic tremor

Answer 23

• Muscarinic receptors (localized to striatal neurons): may cause presynaptic inhibition of dopamine release
• Dopamine deficiency in the striatum augments the excitatory cholinergic system
• blockade of this system by anticholinergic helps alleviate motor dysfunction

Question 24

Trihexphenidyl (Artane) and Benztropine (Cogentin)

Answer 24

• USE: for pts taking neuroleptics as anti-dopaminergic properties of these drugs antagonize effects of levodopa, improve muscle rigidity and tremor (little effect on bradykinesia)
• ADR: Atropine like (dry mouth, inability to sweat, impaired vision, urinary retention, constipation, drowsiness, confusion)

Question 25

Parkinson’s Treatment Recommendations

Answer 25

1. Selegiline for initial mild PD treatment
2. Levodopa or Dopamine agonist
   - Levodopa improves motor disability (safe, does not accelerate dz progression)
   - Dopamine agonist better to decrease risk of motor complications
3. Alternative therapies with some evidence: exercise, speech therapy

• no improvement with Vit E