Term
| List some symptoms of Parkinson's Disease |
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Definition
Parkinson's Disease is a hypokinetic disorder stemming from degeneration of dopaminergic neurons and the loss of their influence of the basal ganglia. Initiation of motor function is impaired.
Symptoms include:
Shuffling Gait
Mask Facies
Pill Rolling Tremor
Cog-Wheel Rigidity
"Freezing"
Micrographia |
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Term
| What drugs may precipitate parkinsonism, thereby causing Iatrogenic Parkinson's Disease? |
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Definition
Neuroleptics (antipsychotics), which are D2 antagonists, may cause symptoms of parkinson's disease. Notable neuroleptics include Chlorpromazine and Haloperidol. This is reversible on withrawal of the drug.
Reserpine, which depletes monoamine stores, can also lead to parkinson's. Recall that it prevents uptake of monoamines (including dopamine) into vesicles. This leaves them vulnerable to metabolism by MAOs, which gobbles them up.
MPTP is a contaminant in meperidine synthesis. MAO B metabolizes this to the toxic product MPP. (deprenyl/selegiline blocks MAO B and would thus prevent MPP production from MPTP) |
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Term
| What is the MoA of Selegiline? |
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Definition
Selegiline is a monoamine oxidase B inhibitor (MAO B).
MAO B is an enzyme that breaks down dopamine into its metabolites. Its inhibition keeps dopamine levels higher, slowing the disease symptoms. Additionally, by inhibiting dopamine breakdown, you inhibit the process of free radical formation that accompanies it. Free radicals speed up the destruction of the cells. This means that selegiline is also protective to the neurons.
In younger patients with PD, the MAOI (selegiline) and D2 agonist (bromocriptine/cabergoline) combination therapy is preferred because L-Dopa/carbidopa carries with it more unwanted side effects (especially when given as long-term treatment where their levels can build up). Save the L-Dopa/carbidopa for older patients with more advanced disease. |
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Term
| What is the benefit of sustained release L-Dopa/Carbidopa? |
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Definition
| By maintaining plasma levels, the sustained release preparation minimizes the "end of dose" freezing experienced with normal dosing schemes. |
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Term
| What is the MoA of Carbidopa? |
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Definition
| Carbidopa inhibits peripheral aromatic aminoacid (L-Dopa) decarboxylase. Carbidopa does not cross the BBB, so it does not block this enzyme in the CNS. This prevents L-dopa metabolization in the periphery, keeping its plasma levels high and facilitating its entry into the CNS. It then is able to be metabolized in the CNS to dopamine! (because the decarboxylase is not inhibited here!) |
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Term
| You have a patient on L-dopa/carbidopa and you want to increase their dopamine levels even further. WHat do you do? |
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Definition
| You can't just give more and more L-dopa/carbidopa because these lead to toxicities and adverse effects. Instead, give a COMT inhibitor like Entacapone or Tolcapone. |
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Term
| What dietary supplement must not be taken by patients receiving carbidopa therapy? |
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Definition
| Pyridoxal phosphate, because this drug is a cofactor for the L-Dopa decarboxylase enzyme and inhibits the binding/action of carbidopa. |
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Term
| Why give L-Dopa and carbidopa together? |
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Definition
L-Dopa can be metabolized peripherally by L-Dopa decarboxylase. This will greatly reduce the amount of L-Dopa available to cross into the CNS. Recall that L-Dopa is converted to dopamine, but dopamine is unable to cross the BBB into the CNS, where it is needed.
By inhibiting the decarboxylase enzyme, the levels of L-Dopa available to cross the BBB are greatly increased! |
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Term
| when would you give tolcapone or entacapone? |
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Definition
| These drugs are COMT inhibitors. Give them to someone on L-Dopa/Carbidopa therapy when you want to increase their dopamine levels even further. Recall that L-Dopa is converted peripherally to Dopamine by the decarboxylase inhibited with carbidopa. But it is also metabolized to 3-O-methyldopa by COMT. SO we can now doubly inhibit its metabolization by giving the COMT inhibitors on top of the L-Dopa/Carbidopa therapy. These COMT inhibitor drugs are not used unless the patient is already on L-dopa/carbidopa. |
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Term
| What are some side effects of L-Dopa therapy? |
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Definition
When they first take the pill and when the pill wears off there may be peak dose (choreoathetoid) and end of dose dyskinesias, respectively.
At the end of the dose there may be "end of dose deterioration" and on/off switching. Here, when the dose wears off, the patient is suddenly unable to move, making them socially dysfunctional. This is a benefit of the sustained-release preparations of L-dopa/carbidopa, in which the "end of dose" phenomena are minimized.
There may also be hallucinations, delusions, confusion |
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Term
| What drugs can be used to help minimize the end of dose dyskinesias felt by parkinson's patients on L-Dopa? |
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Definition
Sustained release preparations of L-dopa/carbidopa
Addition of longer half-life D2 agonists (bromocriptine/cabergoline) to create an overarching canopy that will maintain dopamine activity between the end of one L-dopa dose and the begining of another.
The addition of a COMT inhibitors (entacapone, tolcapone) maintains higher L-Dopa levels by slowing down its metabolism into 3-O-methyldopa.
Deep brain stimulation |
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Term
| Which dopamine agonist has the longest half-life? |
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Definition
Cabergoline has a 65h half-life!
Other dopamine agonists include the relatively short-lived bromocriptine (3-6h) and the intermediate pramipexole (8-12h)
Cabergoline has a higher incidence of dyskinesias. |
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Term
| What are some potential adverse effects of the dopamine agonists? |
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Definition
Pulmonary/retroperitoneal fibrosis and valvular heart disease may result from long-term use of dopamine agonists like bromocriptine or cabergoline.
They may also produce psychoses |
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Term
| What class of drug do trihexylphenidyl, orphenadrine, and benztropine fall under? |
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Definition
| These are all anticholinergic drugs used in parkinson's disease. They are useful in preventing the pill-rolling tremor associated with the disease. |
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Term
| Which COMT inhibitor carries with it the risk of liver failure? |
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Definition
| Tolcapone can cause liver failure. |
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Term
| Which COMT inhibitor blocks L-dopa conversion to 3-O-methyldopa in the CNS? |
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Definition
Tolcapone inhibits COMT in both the CNS and periphery. Entacapone preferentially inhibits this enzyme in the periphery.
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