Parkinson's Disease: Basics

Question 1

What is the primary deficit in Parkinson’s Disease?

Answer 1

Loss of the neurons in the substania nigra pars compacta which provide dopaminergic innervation to the striatum

Question 2

Dopamine as well as all catecholamines in the nervous system originates from what AA precursor?

Answer 2

Tyrosine

–transported by system L across the blood brain barrier in a Na independent manner

Question 3

Once tyrosine gains entry into the neuron the rate limiting step in the dopamine synthesis is?

Answer 3

Conversion of L tyrosine to L -DOPA

—by the enzyme tyrosine hydroxylase

Question 4

DOPA is converted to dopamine by aromatic L amino acid decarboxylase (DOPA carboxylase). This latter enzyme turns over so rapidly that what happens?

Answer 4

DOPA levels in the brain are negligible under normal conditions
–it is possible to enhance the formation of dopamine by providing this enzyme with increased amounts of substrate

Question 5

Once synthesized, what happens to dopamine?

Answer 5

Dopamine is sequestered in storage vesicles
–the vesicular monoamine transporter 2 (VMAT2) is responsible for transporting dopamine into vesicles for subsequent release.
Release of dopamine from nerve terminals occurs through exocytosis of presynaptic vesicles, a process triggered by depolarization leading to Ca2+ entry.

Question 6

The actions of dopamine are terminated by reuptake into the nerve terminal or uptake into the postsynaptic cell. Metabolism occurs by the sequential actions of COMT, MAO and aldehyde dehydrogenase. In humans, what is the principle metabolite of dopamine?

Answer 6

HVA

Question 7

The actions of dopamine in the brain are mediated by a family of dopamine receptors. D1 and D2 receptors are abundant in the striatum and are the most important receptor site with regard to causes and treatment of Parkinson’s Disease. Explain the dopamine receptors activation?

Answer 7

1. D1 receptors activate adenylyl cyclase
2. D2 receptors inhibit adenylyl cyclase, activate K currents and suppress Ca currents.
   - -drugs depend mostly on the stimulation of D2 receptors

Question 8

The substania nigra is the source of dopaminergic neurons that terminate in the striatum. What do the dopaminergic neurons do?

Answer 8

Dopaminergic neurons originating in the substania nigra normally inhibit the GABAergic output from the striatum
Cholinergic neurons stimulate the GABAergic output from the striatum

Question 9

In Parkinson’s Disease what happens to the neurons?

Answer 9

There is destruction of the neurons in the nigrostriatal pathway responsible for secreting dopamine in the striatum

Question 10

Many of the symptoms of parkinsonism reflect what?

Answer 10

Imbalance between the excitatory cholinergic neurons and the diminished number of inhibitory dopaminergic neurons

Question 11

What drugs or pathologies cause secondary parkinsonism?

Answer 11

Follow viral encephalitis or multiple small vascular lesions
Classical Antipsychotic drugs (do not give these drugs to parkinson patients)

Question 12

What is the strategy of treatment for parkinson’s disease?

Answer 12

Aimed at restoring dopaminergic input in the basal ganglia and/or antagonizing the excitatory effect of cholinergic neurons

Question 13

What are the drugs used in Parkinson’s Disease?

Answer 13

Drugs that Restore Dopamine Actions
1. Dopamine Precursors: Levodopa
2. Dopamine Receptor Agonists: Ergot Dopamine Agonists (Bromocriptine) and Non-Ergot Dopamine Agonists ( Pramipexole, Ropinirole, Rotigotine and Apomorphine)
3. Inhibitors of Dopamine Metabolism: MAOI ( Selegiline and Rasagiline) and Catechol-O-Methyltransferase Inhibitors ( Tolcapone and Entacapone)
4. Amantadine
Antagonist of AcH
–Antimuscarinics (Benztropine and Trihexyphenidyl)

Question 14

First drug to discuss is the dopamine precursor, Levodopa. What does levodopa do?

Answer 14

Restores dopamine levels in the extrapyramidal centers.

• -in patients with early disease, the number of residual dopaminergic neurons in the substantia nigra is adequate for conversion of levodopa to dopamine.
• -as the disease progresses the number of neurons decrease and there are fewer cells capable of taking up exogenously administered levodopa and converting it to dopamine for storage and release

Question 15

What is the MOA for levodopa?

Answer 15

Transported into the CNS and is converted to dopamine in the brain
–transported via L transport system (also transport system for phenylalanine, tyrosine, tryptophan, leucine, isoleucine, methionine, valine and histadine
A large fraction of levodopa is decarboxylated to dopamine by L-dopa decarboxylase in the periphery

Question 16

When levodopa is used it is generally given in combo with carbidopa. What does this drug do?

Answer 16

Dopa Carboxylase Inhibitor
–does not cross the BBB
–decreases the metabolism of levodopa in the GI tract and peripheral tissues, thus increasing availability of levodopa to the CNS
Sinemet is the combo name

Question 17

What are the pharmacokinetics for Levodopa?

Answer 17

1. Certain AA from ingested food can compete with the drug for absorption from the gut and for transport from the blood to the brain
2. Urine Metabolites: HVA and DOPAC
3. Only about 1/3rd of administered levodopa actually enters the brain unaltered, however, when given with carbidopa the peripheral metabolism is reduced and plasma levels of levodopa are higher, plasma half life is longer and more dopa is available for entry into the brain

Question 18

What are the clinical uses for Levodopa + Carbidopa?

Answer 18

Reduces the severity of the symptoms in the first few years of treatment
–however responsiveness to levodopa may ultimately be lost completely, perhaps because of the disappearance of dopaminergic nigrostriatal nerve terminals
Does not stop progress of Parkinson’s

Question 19

What are the adverse effects of Levodopa?

Answer 19

GI effects: nausea and vomiting
CV effects: tachy and ventricular extrasystoles
CNS effects: Visual and Auditory Hallucinations and Dyskinesia: mood changes, depression and anxiety.

Question 20

What are the wearing off reactions or end of dose akinesia?

Answer 20

Off periods are marked by akinesia alternate over the course of a few hours with on periods of improved mobility but often marked dyskinesia.
–for patients with severe off periods who are unresponsive to other measures apomorphine SQ may provide benefit.

Question 21

What are interactions and contraindications for Levodopa use?

Answer 21

Vitamin B6 is a cofactor for L Dopa decarboxylase (increases peripheral metabolism of levodopa and decreases its effectiveness)
HTN crisis with administration of MAOI
Do not give to psychotic patient s
Do not give to patients with angle closure glaucoma
Arrhythmias can occcur
Do not give antipsychotic drugs
Do not give in patients with active peptic ulcers
Levodopa is a precursor of skin melanin and may activate malignant melanoma

Question 22

Next set of drugs are dopamine agonists, ergot and nonergot derivatives. How are these drugs different then levodopa?

Answer 22

Unlike levodopa they do not require enzymatic conversion for activity, therefore they do not depend on the functional capacities of the nigrostriatal neurons

Question 23

The only ergot derivative to discuss is Bromocriptine. Which is a drug we have discussed before. What is the role of this drug in Parkinson’s Disease?

Answer 23

D2 agonist
–widely used to treat parkinson’s disease and has been used for hyperprolactinemia
AE:
–pulmonary infiltrates, pleural and retroperitoneal fibrosis and erythromelalgia

Question 24

The other class of dopamine agonists are the nonergot dopamine agonists. lets discuss each drug. First is Pramipexole.

Answer 24

Affinity for D3 receptors

• -effective when used as monotherapy for mild parkionson’s
• -also effective in patients with advanced disease, permitting the dose of levodopa to be reduced

Question 25

Next nonergot dopamine agonist is Ropinirole. what are some features?

Answer 25

Pure D2 receptors agonist

• -effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations.
• metabolized by cytochrom P450

Question 26

The third nonergot dopamine agonist is Rotigotine. What are some features?

Answer 26

Tx of early Parkinson’s Disease

–transdermal formulation

Question 27

What are adverse effect of Nonergot Dopamine Agonist?

Answer 27

1. GI effects: nausea, vomiting, constipation, bleeding from peptic ulcer
2. CVS effects: postural hypotension, arrhythmias and painless digital vasospasm (long term treatment)
3. Dyskinesias: abnormal movement similar to those introduced by levodopa may occur
4. Mental Disturbances: Confusions, Hallucinations
5. Uncontrolled somnolence

Question 28

What are the contradictions for dopamine agonists?

Answer 28

Patients with history of psychotic illness or recent MI

–avoid in patients with peripheral vascular disease or peptic ulceration

Question 29

There is a drug called, Apomorphine, used for rescue therapy. what does this mean?

Answer 29

Nonergot Dopaminergic Agonist
–tx of off episodes of akinesia in patients on dopaminergic therapy
Pretreat with Trimethoenzamide (highly emetogenic) or oral domperidone

Question 30

What are contraindications for Apomorphine?

Answer 30

5-HT3 receptor antagonist are contraindicated because the combination can cause profound hypotension and LOC
AE:
–QT prolongation