Pharmacotherapies for Movement Disorders Flashcards
What are the clinical features of movement with Parkinson’s disease?
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
What are festination and retropulsion?
Festination - falling forward
Retropulsion - falling backward
What is the early presentation of Parkinson’s?
Unilateral weakness or fatigue, with vocal changes (Tremor) and olfactory loss
What is the primary contributor to falls and depression in PD patients, and what kills them?
Postural instability + dependency depresses them
Death by general wasting, and complications of immobility like pneumonia
What is required for PD to develop and what is found in these neurons?
> 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
How does dopamine influence the basal ganglia to cause Parkinson’s?
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)
What is the cause of most Parkinsonism?
Idiopathic / environmental
Can be due to environmental toxins, infection, oxidative stress (kills DA cells)
Why isn’t levodopa given alone and what is it given with?
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
What is levodopa/carbidopa’s effectiveness at first and why is it not given first line?
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
What are the early and chronic side effects of levodopa/carbidopa, other than longterm dyskinesia?
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
What are the behavioral side effects of levadopa / carbidopa use?
Impulsivity and hypersexuality from stimulation of nucleus accumbens reward center
What is now used as a first line monotherapy instead of levidopa/carbidopa and give two examples of drugs in this class?
Direct acting DA receptor agonists -> thought to have less risk of dyskinesia so there is safety in younger patients.
Pramipexole and ropinirole
What drugs are used to treat nausea associated with dopamine-agonists?
Peripheral DA antagonists: Trimethobenzamide, domperidone
5HT3 antagonist: ondansetron (Zofran)
What is the mechanism of action of selegiline?
Irreversible MAO-B inhibitor, inhibits dopamine metabolism in the brain
What are the adverse effects of MAO-B inhibitors and why might they be preferable to MAO-A inhibitors?
Nausea and orthostatic hypotension
They have less interaction with tyramine-rich foods than MAO-A
What drug class increases dopamine’s halflife and is being given with levadopa / carbidopa?
Catechol-O-methyltransferase inhibitors (breakdown dopamine in the synapse)
Drug: Entacapone
What antiviral drug is used as an anti-Parkinson’s drug? What is it good for?
Amantadine - mechanism unknown
Early treatment of patients, especially those with tremor -> tremor is relatively resistant to dopamine
What anti-muscarinic drug in Parkinson’s is used, what is it good for, and why might it not be used?
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
Why should antipsychotic drugs not be used to treat psychosis in Parkinson’s?
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
What is the best drug to treat parkinsonian psychosis and how does it work?
Pimavanserin
5HT2A inverse agonist with no effect on dopamine receptors. Pure antipsychotic.
What are two methods of surgical reversal of Parkinson’s?
- Ablation of thalamus or basal ganglia to restore movement
- Deep brain stimulation - electrical stimulation of subthalamic nucleus (overactive) or GPi (overactive) to restore movement.
What is the newest therapy being researched for PD?
Neurorestoration - rescue of sick dopaminergic cells (bring the 20% surviving up to 25% to restore function)
-> all other therapies simply treat symptoms
What are the advantages and disadvantages of deep brain stimulation for PD?
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
What drugs should be considered first for treatment of Parkinson’s?
Do no harm drugs:
Antimuscarinic, MAO-B, amantadine as monotherapies
What is second and third line treatment for PD?
2nd line: DA receptor agonist monotherapy
3rd line: L-dopa/carbidopa, adding entacapone when needed
What drug is used in “off” periods as an adjunct therapy and what should be given with it?
Apomorphine
- > D2 agonist
- > give anti-emetics
What is essential tremor?
Common adult neurological tremor with “crescendo tremor” -> worse with intension. It is bilateral and affects hands, neck, and voice
What aggravates and improves essential tremor?
Emotions, hunger, fatigue
Improved by ETHANOL
Why does essential tremor need to be treated?
It is a quality of life issue - whacked out thalamocortical / olivocerebellar loops
What are the nonsurgical treatments of essential tremor which are available?
Propanolol
or
Low dose primadone (or other antiseizure drugs)
What are the surgical treatments for essential tremor in refractory patients?
- Deep brain stimulation of Vim thalamus
- Radiofrequency or gamma knife thalamotomy, unilaterally (done via high intensity ultrasound which requires no craniotomy)
