Parkinson's disease

Question 1

Dopamine synthesis?

Answer 1

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

Question 2

Dopamine receptors involved with Parkinson’s disease?

Answer 2

D1 receptors - Gs (increase adenylyl cyclase)

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

Question 3

Pathophys of parkinson’s disease?

Answer 3

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.

Question 4

Levodopa?

Answer 4

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

Question 5

Carbidopa?

Answer 5

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.

Question 6

Sinemet?

Answer 6

Dopa prep containing Carbidopa AND Levodopa.

Question 7

AE of Levodopa?

Answer 7

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

Question 8

Classes of dopamine receptor agonists?

Answer 8

1. ergot dopamine agonist

2. non-ergot dopamine agonist

Question 9

Bromocriptine?

Answer 9

Ergot dopamine agonist

Pure D2 agonist

Question 10

Pramipexole and Ropinirole?

Answer 10

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

Question 11

Dopamine agonist AE?

Answer 11

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

Question 12

Apomorphine?

Answer 12

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

Question 13

Dopamine metabolism inhibitors?

Answer 13

1. MAOI
2. COMT inhibitors

**metabolize levodopa and dopamine

Question 14

Deprenyl (Selegiline)?

Answer 14

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.

Question 15

Rasagiline?

Answer 15

MAO-B inhibitor approved for tx of PD

Question 16

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

Answer 16

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.

Question 17

Tolcapone and Entacapone?

Answer 17

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)

Question 18

Amantadine with parkinsons disease?

Answer 18

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)

Question 19

Antimuscarinics with parkinsons disease?

Answer 19

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

Question 20

DOC for Parkinson’s disease?

Answer 20

Levodopa + Carbidopa

2nd most effective - dopamine agonists

Adjuvants..

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