Pakinson's Disease and Movement Disorders

Question 1

What are the hallmark signs of Parkinson’s Disease?

Answer 1

Repetitive pin-rolling; persistent tremor; shuffling gait; rigidity; bradykinesia; slowed speech; personality changes; sleep disorder; and cognitive decline.

Question 2

Describe the basic pathophysiology behind Parkinson’s Disease:

Answer 2

Parkinson’s Disease is characterized by a state of low dopamine; this is caused by loss of dopaminergic neurons in the nigro-striatal pathway.

Question 3

How do ACh and dopamine influence GABA release in the brain?

Answer 3

ACh promotes GABA release; whereas dopamine inhibits GABA release.

Question 4

How does dopamine deficiency in Parkinson’s Disease have an impact on GABA levels?

Answer 4

Less dopamine in Parkinson’s disease means that there is an increase in GABA levels.

Question 5

Why must exogenous supplementation involve dopamine’s immediate precursor (levodopa)?

Answer 5

Dopamine itself cannot cross the blood-brain-barrier.

Question 6

What are some other barriers to the optimization of dopamine therapy?

Answer 6

There are a seres of enzymes that affect the use of dopamine and levodopa: DOPA decarboxylase; MAO; and COMT.

Question 7

Describe the three peripheral pathways of levodopa:

Answer 7

(1) Cross the blood-brain-barrier via an amino-acid transporter, and enter the brain; (2) conversion to peripheral dopamine via DOPA decarbxylase; and (3) conversion to 3-OMD by COMT.

Question 8

Why is it bad for levodopa to be converted to dopamine in the periphery by DOPA decarboxylase?

Answer 8

Dopamine in the periphery is bad – (1) this means less levodopa will make it into the brain to have a therapeutic effect; and (2) dopamine in the periphery is the source of many ADRs.

Question 9

Why is is bad for levodopa to be converted to 3-OMD in the periphery by COMT?

Answer 9

This makes less levodopa available to cross the blood-brain-barrier and exert a therapeutic effect.

Question 10

Why must high-protein meals be avoided within 30-60 minutes of taking levodopa?

Answer 10

Because levodopa crosses the blood-brain-barrier via an amino acid transporter; consumption of a high protein meal would create competition at this transporter and lessen the therapeutic effect of levodopa.

Question 11

What are the possible pathways of levodopa once it crosses into the brain?

Answer 11

(1) Conversion to dopamine by DOPA-decarboxylase (desired); (2) or conversion to other metabolites by COMT or MAO-B (limits the therapeutic effect).

Question 12

How does dopamine exert its therapeutic effect in the brain?

Answer 12

Dopamine acts on D2-receptors in the basal ganglia in order to control movement and posture; activation of other dopamine receptors can cause ADRs.

Question 13

What are the therapeutic modalities fr treating Parkinson’s Disease?

Answer 13

(1) L-DOPA; (2) D2-agonists; (3) COMT/MAO-B inhibitors; and (4) muscarinic agonists.

Question 14

What is Sinemet (levodopa/carbidopa)?

Answer 14

Levodopa plus a DOPA decarboxylase inhibitor (carbidopa), whch helps to limit ADRs by preventing the conversion of levodopa to peripheral dopamine.

Question 15

What are the two types of D2-agonists?

Answer 15

(1) Ergo-derivative (bromocriptine); and (2) the non-ergot derivatives (pramipexole and ropinerole).

Question 16

How do D2-agonists compare to L-DOPA?

Answer 16

They have fewer metabolic conversion concerns; better blood-brain-barrier penetration; more selective receptor activation; and less response fluctuation.

Question 17

What is the most common use for D2-agonsts?

Answer 17

They are often used in combination with Sinemet to help reduce the required dose and limit ADRs; the non-ergot D2-agonsts may be used as monotherapy in mild PD, or for the treatment of restless leg syndrome.

Question 18

Why is bromocriptine not commonly used in Parkinson’s Disease anymore?

Answer 18

It is an older drug, is not D2 selective, and has CYP3A4 interactions.

Question 19

What are the current uses of bromocriptine?

Answer 19

Hyperprolactinemia; pituitary adenomas; cocaine withdrawal; and alcohol dependence.

Question 20

What are the ADRs of D2-agonists?

Answer 20

GI upset, cardiovascular concerns, dyskinesias, and mental disturbances; use caution in those with psychotic tendencies, recent MI, or uncontrolled hypertension.

Question 21

What percent of L-DOPA makes it into the brain?

Answer 21

Only 1-3%; this is why an enzyme inhibitor is necessary.

Question 22

How is Sinemet typically dosed?

Answer 22

3-4 times a day; 30-60 minutes before meals; and with minimal protein intake – this creates compliance concerns.

Question 23

What are the ADRs of Sinemet?

Answer 23

N/V (common; take with small meal); cardiovascular concerns due to the conversion of dopamine to norepinephrine (tachycardia/hypertension); depression, anxiety, and dyskinesia (very common).

Question 24

What are the two types of response fluctuation seen with Sinemet?

Answer 24

(1) End-of-dose akinesia (doe wears off more quickly); and (2) on/off phenomenon (unrelated to dose-timing).

Question 25

When does Sinemet have the greatest efficacy?

Answer 25

During the first 3-4 years of treatment; some clinicians may withhold Sinemet while the disease is mild.

Question 26

How does Talcapone work?

Answer 26

It inhibits both central AND peripheral COMT, preventing the conversion of L-DOPA to 3-OMD (Note: central inhibition has not been shown beneficial).

Question 27

What is the most concerning ADR of Talcapone?

Answer 27

Hepatotoxicity (this does not occur with entacapone).

Question 28

How does entacapone work?

Answer 28

Inhibits peripheral COMT only, preventing the conversion of L-DOPA to 3-OMD in the periphery; it may be used in combination with Sinemet (Stalevo).

Question 29

What is Stalevo?

Answer 29

L-DOPA + carbidopa (DOPA-decarboxylase inhibitor) + entacapone (COMT-inhibitor).

Question 30

What are the two MAO-B inhibitors?

Answer 30

Selegine and Rasagiline.

Question 31

How do the MAO-B inhibitors work?

Answer 31

They inhibit the enzyme responsible dopamine metabolism, thus, increasing dopamine levels.

Question 32

What is the biggest concern with the MAO-B inhibitors?

Answer 32

They have the ability to increase endogenous serotonin as well; they can cause serotonin syndrome if taken with SSRIs.

Question 33

What two anti-muscarinics are used as adjunctive therapy in Parkinson’s Disease?

Answer 33

Benztropine and Trihexyphenidyl; they are used to help relieve tremor and rigidity.

Question 34

What is apomorphine?

Answer 34

A potent, injectable dopamine agonîst used as a rescue drug from off periods; onset is rapid, but significant nausea limits its clinical use.

Question 35

What is Huntington’s Disease?

Answer 35

An inherited disorder characterized by progressive chorea and dementia; related to an imbalance of dopamine, ACh, and GABA in the basal ganglia.

Question 36

What is the underlying pathophysiolgy of Huntington’s Disease?

Answer 36

Overactivity of dopamine in the nigro-striatal pathway, and reduced/impaired GABA activity; drugs seek to impair dopamine transmission, or block dopamine receptors.

Question 37

What is respirine?

Answer 37

A drug which reduces reuptake of catecholamines, and destroys storage vesicles; it has many ADRs (hypotension, sedation, depression).

Question 38

What is tetrabenazine?

Answer 38

A drug which depletes dopamine stores and mildly antagonizes dopamine receptors.