neuroleptics -> haloperidol

metoclopramide -> DA Antagonist

Reserpine -> Depletes DA, NE

Carbamazepine -> Antiepileptic

MPTP -> neurotoxin, analog of meperidine

High concentrations normally but low

concentrations in Parkinsons

1. tremor

2. rigidity

3. bradykinesia / akinesia

4. disorders of gait and posture

1. Tremor

2. Rigidity

3. bradykinesia/akinesia

4. disorders of gait and posture

1. first motor sign in 75% of patients pill rolling

2. increased resistance to passive movement. ratchety "cogwheel" motion.

3. slowness or absence of movement. drooling. masklike expressionless face w/ decreased blinking

4. festinating (catching up). freezing propulsion falling

degeneration of Dopimanergic neurons in substantia nigra w/in basal ganglia leads to reduction of DA in the striatum.

The Nigrostriatal Pathway is part of the extrapyramidal system that regulates fine motor movement, muscle tone, and posture.

it modifies the output of descending motor pathway to turn gross uncoordinated movement into finely coordinated movements

dopamine is polar and does not cross BBB, thus this drug is given.

rapidly absorbed from SI by active transport. Take on empty stomach. competes for active transport. 1st pass effect. thus only 1% enters CNS. give w/ carbidopa (an inhibitor of dopamine decarboxylase)

prodrug. interacts w/ D2.

GI - NV and anorexia (give w/ carbidopa) CV - tachycardia, arrhythmias, postural hypotension

"wearing off" or "end of dose" akinesia

-decrease w/ COMT inhibitors or Stalevo

"on off phenomenon" --> dyskinesia during on periods.

-decrease protein intake

-fluctuations may be lessened by taking smaller doses or prolonged release (Sinemet CR)

Best results in first 3 to 4 years.

- after that refractoriness may develop or increased SE due to supersensitivity

- reserved for more advanced parkinsonism

- abrupt withdrawal causes severe akinesia

This drug is available alone or in fixed dose combos w/ levodopa.

sinemet - slower onset, longer duration.

sinemet cr -controlled release prep 

carbidopa + levodopa allows you to 

- decrease levodopa dose by 75%

- NV less freq

- tachycardia less likely

-less fluctuation

- pyridoxine no longer antagonizes L-dopa

L-dopa alone - only 3% reaches CNS

L-dopa w/ carbidopa - 10% reaches CNS

dyskinesias and psychiatric disturbances develop earlier and can be more severe

start low doses and increase gradually

caution: peptic ulcer, cardiac disease, open angle glaucoma (mydriasis)

contraindications: angle closure glaucoma, psychosis, malignant melanoma (L-dopa is a precursor to melanin)

Drug interactions:

-pyridoxine

-MAO inhibitors (can cause hypertensive crisis)

dopaminergic agonist

ergoline. used to treat hyperprolactinemia.

strong D2 agonist, weak D1 agonist

effects = Ldopa but weaker. works better when used w/ Ldopa.

combined w/ Ldopa for "on off" phenom or "refractoriness"

alternative to Ldopa if contraindicated

SE

-CV - orthostatic hypotension

-dyskinesias - less than Ldopa

- more confusion

-erythromelalgia (red, tender lower extremities)

contraindications

-mental illness, CV disease, pregnancy

start low dose

Pramipexole

Ropinirole

Rotigotine (transdermal patch)

Nonergot DA agonists

selective D2 agonist

Pram - excreted unchanged in urine

Rop - CYP1A2

alone for mild disease or in combo w/ Ldopa for advanced disease

to treat --> Restless Leg syndrome (more common in women)

SE --> sudden sleep attacks during daytime

MAO-B inhibitor

lacks undesirable effects of non-selective MAO inhibitors

may have neuroprotective & anti-apoptotic effects

alone for early disease or adjunct w/ Ldopa for advanced disease. may decrease mild "on off" or "wearing off" phenom

SE --> dyskinesias & mental disturbances

RxInteraction

-SSRI's - increase serotonin syndrome

-Meperidine - rigidity, agitation, delirium, tremens

Tolcapone

(The Com Told Capone not to Drink Too Much or else his liver would fail)

COMT inhibitor

half life 2 hrs so given 4 to 6 times a day

adjunct to Ldopa

Adverse

- ND, hypotension

- Hepatotoxicity (Tolcaprone only)

originally antiviral drug for Type A influenza

MOA

-increase DA release

-blocks DA reuptake

-blocks NMDA-Glutamate R

Adverse reactions

-CNS

-Livedo Reticularis - vasospastic disease (fishnet appearance)

Trihexyphenidyl (prototype)

Benztropine mesylate

blocks central M-1 receptor

anticholinergic drug - decrease cholinergic activity from striatal neurons

Adverse reaction - confusion.

dry mouth, cycloplegia

Use - younger patients with mild early disease or drug induced parkinsonism

-adjunctive therapy w/ Ldopa

-Tremor and rigidity most improved but not bradykinesia

1. Cortex sends excitatory Glutaminergic NT to the Striatum

2. Striatum send Direct Inhibitory GABA to Globus Pallidus (GP) and Substantia Nigra pars reticulata (SNpr)

3. This causes GP & SNpr to stop inhibiting the Thalamus

4. Thalamus provides excitatory Glutamate to Cortex to promote movement

1. Cortex excites Striatum w/ Glutamate

2. Striatum sends inhibitory GABA to GP

3. GP send GABA to subthalamic nucleus (STN) and disinhibits it

4. STN sends excitatory Glutamate to SNpr

5. SNpr sends GABA to Thalamus to inhibit movement

1.  SNpc provides DA to striatum

2. DA excites the direct pathway via D1 and inhibits the indirect pathway via D2

3. In Parkinson's there is degeneration of DA neurons in SNpc thus depletion of DA

-This leads to overactivity of the indirect pathway 

-which increases the glutaminergic activity of the STN

- this leads to increased inhibition of thalamus and decreased excitatory input to motor cortex

-Thus HYPOKINESIA