Pharmacotherapies for Movement Disorders

Question 1

What are the clinical features of movement with Parkinson’s disease?

Answer 1

Bradykinesia - slowness and difficulty initiating movement

Cogwheel muscle rigidity

Resting tremor - pill-rolling motion, opposite of intention tremor

Impairment of postural stability with festination and retropulsion

Question 2

What are festination and retropulsion?

Answer 2

Festination - falling forward

Retropulsion - falling backward

Question 3

What is the early presentation of Parkinson’s?

Answer 3

Unilateral weakness or fatigue, with vocal changes (Tremor) and olfactory loss

Question 4

What is the primary contributor to falls and depression in PD patients, and what kills them?

Answer 4

Postural instability + dependency depresses them

Death by general wasting, and complications of immobility like pneumonia

Question 5

What is required for PD to develop and what is found in these neurons?

Answer 5

> 80% loss of nigrostriatal dopamine supply (other areas are impacted as well)

Lewy bodies are found in these neurons

PNS can also be affected with dopamine deficiency

Question 6

How does dopamine influence the basal ganglia to cause Parkinson’s?

Answer 6

Typically D1 receptors are on the direct pathway and are Gs excitatory, D2 receptors on the indirect pathway and are inhibitory.

Dopamine will preferentially active the direct pathway, which promotes movement. When this is absent, indirect pathway predominates and movement stops

(no more motor signals to cortex via VA/VL thalamus)

Question 7

What is the cause of most Parkinsonism?

Answer 7

Idiopathic / environmental

Can be due to environmental toxins, infection, oxidative stress (kills DA cells)

Question 8

Why isn’t levodopa given alone and what is it given with?

Answer 8

It is primarily decarboxylated peripherally if given alone -> less than 1% would reach brain

Now given with “carbidopa” - aromatic amino acid decarboxylase inhibitor in the periphery

Question 9

What is levodopa/carbidopa’s effectiveness at first and why is it not given first line?

Answer 9

Super effective at first, better for bradykinesia than tremor

Has reduced efficacy after 2-5 years, and dyskinesias develop in 80% of patients after the fact

Question 10

What are the early and chronic side effects of levodopa/carbidopa, other than longterm dyskinesia?

Answer 10

Early: Nausea and vomiting due to area postrema stimulation, anorexia from hypothalamic stimulation, and orthostatic hypertension

Chronic: sleepiness, and hallucinatory / dementia-related CNS effects, particularly in patients already with dementia

Question 11

What are the behavioral side effects of levadopa / carbidopa use?

Answer 11

Impulsivity and hypersexuality from stimulation of nucleus accumbens reward center

Question 12

What is now used as a first line monotherapy instead of levidopa/carbidopa and give two examples of drugs in this class?

Answer 12

Direct acting DA receptor agonists -> thought to have less risk of dyskinesia so there is safety in younger patients.

Pramipexole and ropinirole

Question 13

What drugs are used to treat nausea associated with dopamine-agonists?

Answer 13

Peripheral DA antagonists: Trimethobenzamide, domperidone

5HT3 antagonist: ondansetron (Zofran)

Question 14

What is the mechanism of action of selegiline?

Answer 14

Irreversible MAO-B inhibitor, inhibits dopamine metabolism in the brain

Question 15

What are the adverse effects of MAO-B inhibitors and why might they be preferable to MAO-A inhibitors?

Answer 15

Nausea and orthostatic hypotension

They have less interaction with tyramine-rich foods than MAO-A

Question 16

What drug class increases dopamine’s halflife and is being given with levadopa / carbidopa?

Answer 16

Catechol-O-methyltransferase inhibitors (breakdown dopamine in the synapse)

Drug: Entacapone

Question 17

What antiviral drug is used as an anti-Parkinson’s drug? What is it good for?

Answer 17

Amantadine - mechanism unknown

Early treatment of patients, especially those with tremor -> tremor is relatively resistant to dopamine

Question 18

What anti-muscarinic drug in Parkinson’s is used, what is it good for, and why might it not be used?

Answer 18

Benztropine

Good for TREMOR and rigidity (like amantadine), but not bradykinesia (balances acetylcholine with dopamine in BG)

Not used because it has lots of CNS effects in elderly, who tends to have parkinson’s

Question 19

Why should antipsychotic drugs not be used to treat psychosis in Parkinson’s?

Answer 19

Because antipsychotic drugs all block dopamine as well -> worsen Parkinson’s. Only clozapine would be a reasonable choice for this indication because it is a 5HT2A antagonist

Question 20

What is the best drug to treat parkinsonian psychosis and how does it work?

Answer 20

Pimavanserin

5HT2A inverse agonist with no effect on dopamine receptors. Pure antipsychotic.

Question 21

What are two methods of surgical reversal of Parkinson’s?

Answer 21

1. Ablation of thalamus or basal ganglia to restore movement
2. Deep brain stimulation - electrical stimulation of subthalamic nucleus (overactive) or GPi (overactive) to restore movement.

Question 22

What is the newest therapy being researched for PD?

Answer 22

Neurorestoration - rescue of sick dopaminergic cells (bring the 20% surviving up to 25% to restore function)

-> all other therapies simply treat symptoms

Question 23

What are the advantages and disadvantages of deep brain stimulation for PD?

Answer 23

Advantages - reversible (versus thalamic ablation) and adjustable, fewer complications

Disadvantages - surgical risks, slight decrease in cognition has been shown, also does not change postural instability

Question 24

What drugs should be considered first for treatment of Parkinson’s?

Answer 24

Do no harm drugs:

Antimuscarinic, MAO-B, amantadine as monotherapies

Question 25

What is second and third line treatment for PD?

Answer 25

2nd line: DA receptor agonist monotherapy

3rd line: L-dopa/carbidopa, adding entacapone when needed

Question 26

What drug is used in “off” periods as an adjunct therapy and what should be given with it?

Answer 26

Apomorphine

• > D2 agonist
• > give anti-emetics

Question 27

What is essential tremor?

Answer 27

Common adult neurological tremor with “crescendo tremor” -> worse with intension. It is bilateral and affects hands, neck, and voice

Question 28

What aggravates and improves essential tremor?

Answer 28

Emotions, hunger, fatigue

Improved by ETHANOL

Question 29

Why does essential tremor need to be treated?

Answer 29

It is a quality of life issue - whacked out thalamocortical / olivocerebellar loops

Question 30

What are the nonsurgical treatments of essential tremor which are available?

Answer 30

Propanolol

or

Low dose primadone (or other antiseizure drugs)

Question 31

What are the surgical treatments for essential tremor in refractory patients?

Answer 31

1. Deep brain stimulation of Vim thalamus
2. Radiofrequency or gamma knife thalamotomy, unilaterally (done via high intensity ultrasound which requires no craniotomy)