• nigrostriatal projection
  • substantia nigra projecting to striatum
• mesocorticolimbic system
  • VTA projecting to nucleus accumbans and frontal cortex

• too much dopamine is being released

• akinesia (ex: bradykinesia in lesser level)
• tremor (ex: pill rolling gate)
• rigidity (ex: cogwheel type)
• impairment of postural balance (ex: disturbances in gait and falling)
• shuffling gait
• loss of assoc.

1. striatum has two inputs
   • substantia nigra via dopamine (dies in parkinsons)- inhibitory
   • cholinergic influence via ACh- excitatory
2. striatum has one output to the globus pallidus via GABA and substance p- inhibitory
3. globus pallidus also has an input from subthalamic nucleus via Glu- excitatary
4. globus pallidus has two outputs
   1. subthalamic nucleus via GABA- inhibitory
   2. thalamus via GABA- inhibitory
5. thalamus to cortex- excitatory
6. gl

• inhibits MAO-B, leading to the prevention of Parkinsonism in monkeys
• this is what we use to study Parkinson's

1. orally absorbed
   1. 70% metabolized in the GI tract
   2. the rest goes to the tissue
2. from the tissue, its fate is:
   1. 95% decarboxylated in periphery
   2. the rest crosses the BBB and is convereted to dopamine

This will increase the amount of dopamine

• peripheral (produce DA before L-DOPA get into CNS)
  • nausea (stimulate CNS)
  • cardiac arrhythmias (stimulate beta 1)
  • orthostatic hypotension (stimulate peripheral dopamine receptors)
• CNS (increase DA synthesis in CNS)
  • psychotic symptoms (D2 R's in limbic system)
  • dyskinesias
  • on-off phenomenon
    • Parkinson symptoms controlled but still have dyskinesias
    • symptoms not controlled (may have dystonias)

• inhibit COMT and MAO-B within the CNS
• titrate dosage of L-DOPA

• psychosis
• melanoma (L DOPA precursor for melanin)
• narrow angle glaucoma (alpha agonist activity at high conc.)
  • leads to inability of vitreous humor to drain from the Canal of Schlemm

• Pyridoxine enhance extracerebral metabolism of L-DOPA as cofactor for L-AAD (cause peripheral met. of L-DOPA) 
  • CI: Vitamin B6
• nonselective MAO inh. prevent metabolism of dopamine, causing a risk of HTN crisis
  • CI: nonselective MAO inh.
• antipsychotics (D2 blockers) antagonize therapeutic effects of L-DOPA
  • CI: antipsych.

1. stays in the periphery and blocks L-AA decarboxylase
2. this will prevent breakdown of levadopa in the periphery
   1. leads to increase of levadopa delivery to the brain
   2. BUT there is a compensatory increase in COMT in the periphery

1. inhibits COMT in the periphery
2. crosses the BBB and inhibits COMT in BBB
3. leads to increase in dopamine delivery to the brain

• inhibits COMT only in the periphery (cannot cross the BBB), leading to increase in L-DOPA delivery to the CNS

• COMT inhibitors
  • tolcapone
  • entacapone
• L-AAD inhibitors: carbidopa

• advantages
  • reduce L-DOPA by 75%
  • peripheral side effects due to conversion of L-DOPA to DA diminished
  • reduce on off phenomenon (when reduce metabolism of dopamine, alleviate symptoms)
• disadvantages
  • CNS effects could be worsened (more DA available centrally): dyskinesias, psychotomimesis

• diarrhea
• more liver toxicity than entacapone

• inhibits MAO-B in CNS while leaving MAO-A intact in the periphery (this is the predominant form of MAO in the striatum)

• allows reduction in L DOPA dose
• reduce on off phenomenon

• worsens central side effects
• CI: nonselective MAOI (could lead to HTN crisis due to build up of NE)

• allows L-DOPA does reduction
• alleviates on off phenomenon
• used in patients becoming refractory to L-DOPA

• ergots-bromocriptine
• nonergots
  • ropinirole
  • pramipexole

• peripheral
  • nausea (CTZ)
  • hypotension (via action on D2 R's)
  • solution: add dopamine antagonist that does not cross the BBB
• CNS
  • dyskinesias
  • psychosis

• can be titrated up to full dose more quickly
• fewer GI problems
• in general, better tolerated
• preferred for younger patients (older patients get L-DOPA)

• psychosis
• recent MI
• peripheral vascular disease
• peptic ulcers

• initial Parkinson's therapy
  • short lived therapy (not long term or strong)
  • reduced bradykinesia, rigidity, tremor in early stages

• mild
  • restlessness
  • depression
  • irritability
  • insomnia
  • agitation
  • excitement
  • hallucinations
  • confusion
• OD- acute toxic psychosis

• used in combo with L DOPA
• can be used in very mild Parkinsonism (esp. if tremor is only symptom)- THIS WILL BE ON THE TEST
• works better on tremor and rigidity than bradykinesia- THIS WILL BE ON THE TEST

• central
  • drowsiness
  • mental slowness
  • inattention
  • restlessness
• peripheral
  • dry mouth
  • blurred vision
  • mydriasis
  • urinary retention

• prostatic hypertrophy (already have urinary retention)
• obstructive GI disease
• narrow angle glaucoma