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Flashcards in Parkinson's disease Deck (20):

Dopamine synthesis?

1. Tyrosine transported by system L across the blood brain barrier in the Na+-independent manner
2. tyrosine to Dopa via tyrosine hydroxylase [rate limiting step]
3. dopa to dopamine via DOPA decarboxylase


Dopamine receptors involved with Parkinson's disease?

D1 receptors - Gs (increase adenylyl cyclase)
D2 receptors - Gi (decrease adenylyl cyclase), increase potassium conductance and decreased calcium conductance


Pathophys of parkinson's disease?

Dopaminergic and Cholinergic innervation of GABAergic neurons - dopamine inhibits GABA neurons increasing movement, Cholinergic activates GABA neurons decreasing movement. Destruction of the dopaminergic neurons lead to loss of control of muscle movement. Symptoms first appear when 70% of neurons in the nigrostriatal pathway are destroyed.



Metabolic precursor of dopamine (and NE) that restores dopamine levels in the extrapyramidal centers. In patients with early disease, the number of residual dopaminergic neurons int he substantia nigra is enough for conversion of levodopa to dopamine. Overtime, the number of neurons decrease and there are fewer cells capable of taking up levodopa and converting it to dopamine. Levodopa solely provides symptomatic relief.
Dopamine cannot cross the BBB, but Levodopa is transported into the CNS and can be converted to dopamine in the brain via DOPA decarboxylase.
Another issue is that much of levodopa is decarboxylated to dopamine in the periphery resulting in peripheral side effects (nausea, vomiting, cardiac arrhythmias, hypotension).

Rapid absorption from the SI and food can delay the appearance of levodopa int he plasma. AA can also compete with drug absorption in the gut and BBB.

**COMT and MAO degradation to HVA



Dopa decarboxylase inhibitor that does not cross the BBB and is given in combination with Carbidopa. When given in combination, carbidopa decreases the metabolism of levodopa in the GI tract and peripheral tissue increasing the availability of levodopa to the CNS.



Dopa prep containing Carbidopa AND Levodopa.


AE of Levodopa?

1. wearing-off reactions - end of dose akinesia which can be related to the timing of levodopa so take more frequently at smaller doses
2. The on-off phenomenom - fluctuations in response that are unrelated to the timing of doses, mechanism is unknown and for pts with severe off-periods may take SC apomorphine
3. Vit B6 is required for dopa decarboxylase reaction so do not give with B6 b/c it increases peripheral metabolism of levodopa?
4. do not coadminister with MAOI as it may precipitate a hypertensive crisis
5. Do not give to psychotic patients b/c it may exacerbate the mental disturabance
6. contraindicated in angle-closure glaucoma
7. may lead to possible arrhythmias


Classes of dopamine receptor agonists?

1. ergot dopamine agonist
2. non-ergot dopamine agonist



Ergot dopamine agonist
Pure D2 agonist


Pramipexole and Ropinirole?

Non-ergot dopamine agonist
-used increasingly as initial treatment for PD rather than as adjuncts to levodopa, esp for younger patients
-older patients are more vulnerable to the adverse cognitive effects of dopamine agonist

Rotigotine - available in transdermal formulation given daily


Dopamine agonist AE?

1. GI effects - anorexia, nausea, vomiting, peptic ulcer bleeding
2. CV effects - postural hypotension, cardiac arrhythmias, peripheral edema
3. Dyskinesia - abnormal movements
4. mental disturbance - confusion, hallucinations, delusions
5. ergot dopamine agonists - pulmonary infiltrates, pleural and retroperitoneal fibrosis, erythromelalgia
6. non-ergot dopamine agonists (pramipexole, ropinirole, rotigotine) - uncontrollable somnolence requiring discontinuation of the medication



Nonergot dopamine agonist used for rescue therapy for tx of "off" episodes of akinesia in pts on dopaminergic therapy. It also has emetogenic properties so should be pretreated with the antiemetic, trimtheobenzamide.

AE - QT prolongation, dyskinesias, drowsiness, sweating, hypotension


Dopamine metabolism inhibitors?

2. COMT inhibitors

**metabolize levodopa and dopamine


Deprenyl (Selegiline)?

MAO inhibitor
• Selectively and irreversibly inhibits MAO-B
(which selectively metabolizes dopamine),
• Retards breakdown of dopamine in the brain.
• Enhances effect of levodopa.
• Allows dose of levodopa to be reduced.
• Mainly used as adjunct to levodopa.
• Metabolized to methamphetamine and
amphetamine: may cause insomnia if taken
late in the day.



MAO-B inhibitor approved for tx of PD


Effect of Levodopa administration with dopa decarboxylase inhibitor (Carbidopa)?

DOPA decarboxylase inhibitor prevents metabolism of levodopa in to dopamine. COMT pathway is therefore upregulated to metabolize Levodopa to 3-ortho-methyl dopa which competes with Levodopa for an active carrier that transports levodopa across the intestinal mucosa and BBB. Therefore, you want to inhibit COMT to allow for Levodopa to make it through the BBB.


Tolcapone and Entacapone?

COMT inhibitors that lead to...
1. decreased metabolism of Levodopa
2. decrease plasma levels of 3-O-methyldopa
3. increased Levodopa uptake
4. Higher dopamine levels in the brain

AE - fulminating hepatic necrosis (tolcapone use)


Amantadine with parkinsons disease?

Antiviral drug with anti-parkinsonian action leading to increased synthesis, release or re-uptake of dopamine from the surviving neurons.

AE - Livedo reticularis, restlessness, agitation, confusion, hallucinations, acute toxic pscyhosis @ high doses, peripheral edema (responds to diuretics)


Antimuscarinics with parkinsons disease?

Adjuvant therapy that may improve tremor or rigidity. It has little effect of bradykinesia.

AE - mood changes, xerostomia, pupillary dilation (don't use in pts with glaucoma), confusion , hallucinations, urinary retention


DOC for Parkinson's disease?

Levodopa + Carbidopa

2nd most effective - dopamine agonists

1. COMT Inhibitors and MAO-B inhibitors lead to reduces motor fluctuations in pts with advanced disease.
2. Antimuscarinics - useful for control of tremor and drooling