Drugs For Parkinson's Disease

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L-DOPA

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Dopaminergic
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Purpose: Improves tremor, rigidity, and bradykinesia.
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MOA: L-DOPA crosses the blood brain barrier (1-3% alone), which can then be turned into dopamine by L-amino acid decarboxylase (aka DOPA decarboxylase).
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Adverse Effects: Peripheral – nausea, vomiting, postural hypotention, tachycardia, and arrhythmias.CNS – Fluctuation between classical Parkinsonian symptoms and dyskinesias. Psychosis, mania, hallucinations, sleep attacks, pathologic gambling (treat with atypical antipsychotics – olanzapine – since it has little effect on D2 receptors; MAOi’s are also contraindicated because they enhance the peripheral effects of L-DOPA and can precipitate hypertensive crisis and hyperthermia).
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Notes: Usually combined with carbidopa to decrease adverse effects of L-DOPA turning into Dopamine in the PNS (now 10% of L-DOPA crosses blood-brain barrier) – combo is called “Sinemet". Given PO.

Front 2

Carbidopa

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Purpose: To improve the CNS efficacy of L-DOPA.
________________________________________MOA: Carbidopa inhibits DOPA decarboxylase (that converts L-DOPA to Dopamine) in the periphery since it does not cross the blood-brain barrier.
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Adverse Effects: decreases the peripheral side effects of L-DOPA.
Has no side effects on it’s own.

Front 3

Entacapone
Tolcapone

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COMT Inhibitors
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Purpose: used late in Parkinson’s as an add on to other drugs.
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MOA: Inhibit catechol-O-methyl transferase (COMT) that catalyzes L-DOPA to 3-O-methyl DOPA so more of the L-DOPA can get in the CNS. ]
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Adverse Effects: Tolcapone increases liver enzymes and can rarely cause severe liver disease. Entacapone is not hepatotoxic.
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Notes: Entacapone does not pass the blood-brain barrier so only inhibits peripheral COMT. Tolcapone passes the blood-brain barrier and thus inhibits both brain and peripheral COMT. This difference is not clinically meaningful.

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Amantadine

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Other
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Purpose: ?
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MOA: May effect uptake or release of dopamine while also inhibiting the NMDA glutamate receptors.
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Adverse Effects: Restlessness, depression, irritability, and confusion.
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Notes: Has short-term efficacy but often loses its effectiveness after 6-8 weeks, especially in patients with advanced disease.

Front 5

Benztropine
Trihexyphenidyl

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Anti-Muscarinics
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Purpose: Decreases tremor and rigidity.
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MOA: Muscarinic receptor antagonist. Inhibits acetylcholine. Restore the balance between dopaminergic and muscarinic cholinergic input into the striatum (reduces in dopaminergic input in Parkinson’s cause an excess of cholinergic input).
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Adverse Effects: “Dry as a bone, Blind as a bat, Red as a beet, Mad as a hatter”. Worse in the elderly and in patients with disease-related cognitive effects. In OD can cause hyperthermia and delirium.

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Selegiline

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Other
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Purpose: Used early to possibly delay disease progression (before using L-DOPA). Sometimes combined with other drugs in the later stages.
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MOA: Selective MAO-B inhibitor (that catalyzes reaction from dopamine to DOPAC). Makes it so more Dopamine is around.
________________________________________Adverse Effects: ?

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Treatment Overview

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Early stages (mild symptoms):
Amantadine, Selegiline, Dopamine agonist, Anti-muscarinic
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Middle stages (moderate symptoms and smooth control):
L-DOPA + carbidopa
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Late stages (severe symptoms, fluctuations, dyskinesias):
L-DOPA + carbidopa + COMT inhibitor or any above except antimuscarinics.

Front 8

Pallidotomy

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Surgical lesion is made in part of the globus pallidus.
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Benefits otherwise healthy, cognitively normal patients who initially responded to dopaminergic therapy but whose treatment became limited by drug-related dyskinesias.
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Reduces L-DOPA induced dyskinesias while it can also improve bradykinesia and tremor.

Front 9

Bromocriptine
Pergolide

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Dopamine agonist (traditional)
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Purpose: Adjunct therapy for patients who have developed a reduced response to L-DOPA or have developed motor fluctuations.
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MOA: Bromocriptine is a full agonist for D2 family (D2, D3, D4) and partial agonist for D1 family (D1, D5) and some serotonergic effects. Perfolide activates both D1 and D2.
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Adverse Effects: More likely than L-DOPA to cause hallucinations and confusion. Less likely to cause dyskinesias. Can cause nausea, vomiting, and postural hypotension. Because are ergot alkaloids, can also rarely cause pulmonary fibrosis, retroperitoneal fibrosis, or erythromelalgia (painful paroxysmal dilation of blood vessels of skin).
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Notes: Lack competition with dietary amino acids, no need for CNS metabolizing pathways, and decreased risk for dyskinesias. Less effective than L-DOPA.

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Pramipexole
Ropinirole

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Dopamine agonist (new)
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Purpose: Used as monotherapy in early stage disease. In late stage disease, used in combination with L-DOPA to decrease on-off phenomenon and allows the reduction of L-DOPA dosage by 30%.
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MOA: Ropinirole is selective for D2 receptors. Pramipexole is selective for D3 receptors.
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Adverse Effects: Nausea, dizziness, and somnolence. Dyskniesias, hypotension, and confusion can still limit therapy.
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Notes: Lack competition with dietary amino acids, no need for CNS metabolizing pathways, and decreased risk for dyskinesias. Less effective than L-DOPA.