Parkinson's Disease

45-70 years of age

• genetic link
• toxins, oxidative stress
• environmental factors (pesticides, rural living, well water)
• medications (antipshychotics, antiemetics)

• caffeine
• smoking

We don't produce enough of it

decreased direct pathway stimulation = decreased facilitation of movement

increased indirect pathway stimulation = increased inhibition of movement

70-80% loss of neurons

• bradykinesia
• resting tremor (usually unilateral)
• rigidity
• postural imbalance

• fenestrating gait
• dysphagia
• difficulty rising from sitting
• hypophonia
• diminished arm swing
• hypomimia
• micrographia

• sialorrhea
• sexual dysfunction
• constipation
• incontinence
• diaphoresis
• olfactory disturbances

• anxiety
• apathy
• slow thought process
• depression
• confusion
• hallucinations
• dementia

tremor

Lewy bodies

• dementia ~ 40%
• psychosis ~ 25%
• mild psychotic symptoms ~ 50%
• depression ~ 40%

• improve QOL
• minimize/improve symptoms
• minimize side effects of medication

• exercise (tango is best)
• deep brain stimulation (implanted stimulator)
• implantation of DA secreting tissue in the brain
• glial-derived neurotrophic factor (GDNF)
• occupational therapy
• speech therapy
• support
• diet

decreased DA

• Replace DA
• L-Dopa
• Mimic DA (stimulate the receptors)
• pramipexole
• ropinirole
• bromocriptine
• apomorphine
• pergolide
• Stop the breakdown of DA
• selegiline (MAO-B in brain)
• rasagiline (MAO-B in brain)
• tolcapone (COMT in brain and periphery)
• entacapone (stops breakdown of L-Dopa by COMT in periphery)
• carbidopa (stops breakdown of L-Dopa by Dopa Decarboxylase in periphery)

free radicals

• age
• duration of disease
• dose of medication
• severity of disease

levodopa (L-Dopa)

Carbidopa - inhibits the breakdown of L-Dopa in the periphery by Dopa Decarboxylase

1-3 hrs (duration may exceed half-life during early treatment because the neurons can still absorb and use it)

It works fast (peak in 1-2 hrs)

• short half-life
• waning effect results in "off" periods (motor fluctuations) = even shorter half-life
• may be converted in periphery = increased SE and decreased levels in brain
• dyskinesias
• pharmacokinetic variability
• NAUSEA if broken down in periphery
• competes with proteins for absorption in the gut and for transport across BBB
• absorption affected by GI conditions

• increase dosing frequency
• add entacapone
• add risagiline
• add a DA agonist (apomorphine - only helps for 100 min)

• nausea (tolerance develops; use antacids)
• dyskinesias (as soon as 6 mo; reversible)
• hallucinations
• confusion
• orthostatic hypotension
• no use in pts with psychosis

• use oral disintegrating tablets
• separate from protein
• give apomorphine
• drug holiday

• physical therapy
• increase dose
• add a DA agonist or MAO-B inhibitor

• decrease dose
• give amantadine

• MAO-A inhibitors
• pyridoxine (vitamin B6)

• angle-closure glaucoma
• psychosis

• motor complications
• waning effects
• other classes of drugs are effective

MAO-B inhibitors

irreversible inhibition of MAO-B

• May use as monotherapy in early PD (delays need for L-Dopa)
• modest improvements in motor function
• evidence that rasagiline delays functional decline
• oral disintegrating tablet available

• side effects from active metabolites....methamphetamine, amphetamine (selegiline only)
• may augment motor and cognitive side effects of L-dopa therapy
• interactions with tyramine containing foods (cheddar, tap beer, salami, wine, soy)

major depressive disorder

• anxiety
• insomnia
• hallucinations
• worsens existing psychosis and dyskinesia SE of L-Dopa (selegiline)
• orthostatic hypotension

• may increase risk of serotonin syndrome
• pseudoephedrine and pheynylephrine cause HTN

• TCAs
• meperidine
• dextromethorphan, methadone, propoxyphene, tramadol - with the ODT

Yes, the slowed breakdown of DA may result in less free radicals

• before meals
• last dose should be early in day due to SE

tolcapone and entacapone

prevent peripheral conversion of L-Dopa by COMT

• reduce off time
• combination available with carbidopa/levodopa (entacapone)
• extend duration of activity for L-Dopa
• first line adjunct for motor fluctuations (entacapone)

• cannot be used as monotherapy
• administered up to 8 times daily (entacapone)

• hepatotoxicity (tolcapone)
• delayed onset diarrhea (tolcapone)
• brownish-orange colored urine (tolcapone)
• nausea
• orthostatic hypotension
• dyskinesias

• co-adminster with carbidopa/levodopa
• do not stop abruptly

• fewer motor fluctuations; reduced risk
• well tolerated in younger patients
• longer DOA than L-Dopa
• do not rely on neuronal functional capacity
• monotherapy in mild disease

• frequent dosing
• worsening of L-Dopa induced dyskinesias
• class SE (nausea, neurologic, postural hypotension, compulsive behaviors, hallucinations)

• can titrate faster than ergot derivatives
• safer than ergot derivatives
• well tolerated in younger patients
• duration of action longer than L-Dopa
• potentially less generation of free radicals (d/t less catabolism of DA)
• may be used as initial therapy (monotherapy in mild PD)
• do not rely on neuronal function
• may be taken with food to decrease nausea SE

• tid administration
• worsening of dyskinesias

• somnolence
• nausea
• hallucinations
• dyskinesias
• orthostatic hypotension
• constipation

minimal

potentially (decreased free radicals)

with or without food (may help with nausea)

rapidly triggers "on" response

• adminstered SQ
• severe nausea; premedicate with trimethobenzamide

• nausea/vomiting
• postural hypotension (test dose)
• somnolence

concomittant administration with 5-HT₃ agents (ondansetron, dolasetron, granisetron, palonosetron)

100 min

because decreased levels of DA results in extra ACh (causes EPS - tremor, rigidity; drooling

• minimal improvement of bradykinesia
• elderly are more susceptible to SE of anticholinergics
• no more effective than DA agents

• mad as a hatter
• hot as a hen
• red as a beet
• dry as a bone
• blind as a bat

inhibition of PNS

may increase levels and/or effect of potassium

• narrow angle glaucoma
• use with caution in males with BPH

• L-Dopa
• trihexyphenidyl
• benztropine

it supresses L-Dopa induced dyskinesias

unknown

benefit is short lived

• confusion
• dizziness
• dry mouth
• nausea
• orthostatic hypotension
• edema
• livedo reticularis

may increase levels and/or effect of potassium

• disease duration and severity
• medication use - dose and duration DO NOT MATTER
• depression
• cognitive impairment
• age

• anticholinergics
• MAO-B inhibitors
• amantadine
• DA agonists
• COMT inhibitors
• L-Dopa/carbidopa

• clozapine
• risperidone
• olanzapine
• quetiapine - DOC!!!!
• ziprasidone
• aripiprazole

• selegiline
• L-Dopa
• DA agonist

• delay initiation of L-Dopa if possible
• MAO-B inhibitors for most patients
• DA-agonists for younger patients
• amantadine for dyskinesias

• COMT inhibitors
• MAOB inhibitors
• DA agonists