- PART

- Stands for:  Postural imbalance, Akinesia/Bradykinesia, Rigidity, Tremor at rest

- Marked striatal DA depletion

- At death, > 90% dopamine loss

- <50% dopamine loss is asymptomatic

- ~70% dopamine loss for symptom manifestations

 Treatment:  Dopaminergic agents (Levodopa, Dopamine Agonists), COMT inhibitors, MAO-B inhibitors, anticholinergics, amantidine

Prevention:  Vitamin E, Co Q10, Nicotine

- Decarboxylated in brain to form dopamine

- Gold standard

- Improves rigidity, tremor, bradykinesia, gait, micrographia

- Disadvantages include motor complications, N/V, hallucinations, orthostasis

- Sx not responsive to levodopa include motor (postural instability, freezing), Speech abnormalities, mental changes (Dementia, depression), sensory phenomenon (olfactory), Autonomic (constipation, urinary problems, sweating, sexual dysfunction)

- Blocks peripheral dopa decarboxylase

- Daily dose of 75-100mg

- Increase amount of levodopa entering the brain

- Decrease peripheral adverse effects: N/V, cardiac irritability, orthostasis

- Regular Sinemet onset is 15-30 minutes, , duration of effect is 2-5 hours

- CR Sinemet has onset of 45-60 minutes, duration is 3-8 hours

- Need to give 30% more of CR b/c of reduced absorption

- Intx:  High proteins meals affect absorption, watch timing

- ON-OFF, sudden exacerbations of sx

- Dyskinesia:  Peak dose chorea, athetosis, diphasic, off-period dystonia

- Morning siffness (LOLZ)

- No delayed "on"

- Freezing

- "Wearing off:" Tremor, soft voice, dystonia, sleep fragmentation, bradykinesia

- Carbidopa

- COMT inhibitors

- Dopamine agonists

- MAOB Inhibitors

- Amantadine

- Inhibits Catchol-O-methyl transferase mediated metabolism of dopamine in the blood stream

- Increases levodopa half-life from 2 to 3.5 hours

- Increases area under curve approximately 2x

- No effect on: Cmax or Tmax

- Tolcapone give 100mg with first dose of levodopa then every 6 hours up to 3 doses a day (Max 600mg, liver tox.)

- Entacapone give 200mg with first dose of levodopa than with every additional dose (MDD = 1600mg)

Advantages: Increase "on" time, constant dopaminergic stim., ease of admin. and imm. effect.

Disadvantages:  Levodopa induced dyskinesia, hypotension, GI - nausea and diarrhea, hepatotoxicity with tolcapone urine discoloration

- Stalevo dose corresponds to amount of Levodopa in it, always 1/4 the amount of carbidopa, and always 200mg of entacapone

- Choreiform, ballistic, and dystonic movements

- Manifestation of excessive dopaminergic stimulation

- Typically late effect, and with higher doses

- Narrowing of therapeutic window

- Most common is "peak" dose, disappears with dose reduction

- L-Dopa showed a greater incidence of dopaminergic complications and dyskinesia when compared to Pramipexole and Ropinirole, respectivelyl.

ADR's:  N/v, orthostatic hypotension, HA, confusion, hallucinations, Erythromelalgia; pulmonary and retroperitoneal fibrosis, pleural effusion and thickening, raynaud's phenomenon

- Sleep attacks have been reported

Advantages: 

- Direct effect on receptor

- May delay or reduce motor  fluctuations and dyskinesias, may be neuroprotective

Disadvantages:

- Titration schedule

- SE's include vascular complications from ergot derivatives, other SE's mentioned before

- Stimulates release of dopamine and inhibits reuptake

- Useful adjunct, maybe neuroprotective

- Limited efficacy as monotherapy

- Requires a dose reduction for patients with kidney disease

- Selegeline (Zelapar ODT) and rasagiline (Azilect)

- Motor function early disease

- Advance disease

- Major drug interaction with meperidine (Demerol?)

- Long term outcomes

- Classified as "Rescue" therapy

- SQ injection

- Direct agonist

- Titratable dosage

- Use may be limited to neurology and movement center disorders

- NEVER EVER give with ondansetron, granisetron, dolasetron, palonsetron, and alosetron --> Causes profound hypotension and loss of consciousness

- Most patients respond to 3mg initial dose, titrate with 2mg, do not exceed 6mg daily

- Rule out cardiac arrhythmias

- Pretreatment with domperidone or Tigan

- Anticholinergics may be useful

- Mechanism of action:  Restore balance of Ach/DA by blocking acetylcholine in the basal ganglia

- Address tremor yet not bradykinesia or rigidity

- Do not use in patients at risk of anticholinergic side effects

- Give benztropine 0.5mg hs then increase to MDD of 4-6mg/day

- Or give Trihexyphenidyl 1-2mg/day then increase in increments of 2mg until 6-10mg/day in divided doses

In this order consider.....

1.  Efficacy

2.  Short term side effects

3.  Long term side effects

4.  Cost

Consider the following factors in this order..

1.  Age

2.  Mental status

3.  Co-morbidities

4.  Disease severity

5.  Functional disability

6.  Cost

Dopamine excess:  Dyskinesias, Hallucinations, Delusions

Dopamine Deficiency:  Worsening PD symptoms

- Hypersensitivity of postsynaptic dopamine receptors

- Enhanced serotonin transmission

- Alterations in genetic control

- Premature Lewy Body disease

- False sensory perception

- Usually visual

- Occur in ~30% of drug treated PD patients

- Transient, non-emotion laden

- Insight often present

- Typically recurrent people/animals

- Auditory hallucinations are NOT common

- Anticholinergics

- Selegiline

- Amantadine

- Dopamine Agonists

- COMT inhibitors

- Levodopa/Carbidopa

- Adding 1200mg of Co Q10 with Vitamin E reduced patients' UPDRS after 16 months of treatment (stat. sig.)

- Adding Vitamin E to a therapy will reduce mortality of the Parkinsons patient