Exam 6: Basal Ganglia Pharmacology Flashcards
What is an example of a hypokinetic disorder
Parkinson disease
What is an example of hyperkinetic disorder
Huntington’s disease
What is progressively lost in parkinson disease
Progressive loss of dopaminergic neurons in substantia nigra pars compacta
What does less dopamine in the striatum result in?
Decreased direct pathway activity, increased indirect pathway activity, lose coordinated direct/indirect activity. Marked increase in inhibition of thalamus, reduced excitation of motor cortex
What are the genetic components of Parkinson disease?
alpha-synuclein (SNCA), LRRK2, parkin, others
What are symptoms of parkinson disease?
Bradykinesia, muscle rigidity, resting tremor, impair postural balance
What is the current therapeutic strategy for parkinson’s disease?
treat symptoms only, restoring dopaminergic activity
Why can’t you treat PD patients with dopamine?
It does not cross the BBB
T/F: Levodopa is a prodrug
True
What converts levodopa to dopamine?
L-aromatic amino acid decarboxylase (AAAD)
Why does only 5% of levodopa enter the CNS?
Significant AAAD activity in GI tract
What can high levels of peripheral dopamine cause?
nausea, orthostatic hypertension
What is the action of carbidopa?
inhibits AAAD in the periphery, reducing levodopa dose by nearly 75%
What is Levodopa and Carbidopa called in compound?
Sinemet
What is the mechanism of levodopa
Activates D1 receptors (activates direct pathway), Acivates D2 receptors (inhibits indirect pathway)
When is levodopa most effective in the progression of PD?
early in therapy
What is the overall effect of levodopa on a PD patients disease?
decreased akinesia, rigidity, and tremor
Why is levodopa less effective over time?
progressive loss of dopaminergic neurons
Describe the interaction of L-DOPA and presynaptic neurons
store in presynaptic dopaminergic terminals of striatum and released gradually
What can occur with treatment of L-DOPA as dopaminergic neurons are lost?
dyskinesia
What are dyskinesias?
abnormal involuntary movements
When do “on period dyskinesia” occur?
During times of peak dose (high plasma levels of levodopa) with maximal antiparkinsonian relief
When does diphasic dyskinesia occur while dosing levodopa?
onset and offset of the levodopa effect coinciding rising and falling plasma levodopa levels
What occurs in diphasic dyskinesia?
repetitive, slow movements of the lower limbs often coinciding with tremor in the upper limbs
What occurs during “off” period dystonia?
fixed and painful postures more frequently affecting the feet
What occurs during “on” period dyskinesia
brief, abrupt, irregular, unpredictable movements (chorea) predominantly involving the neck, trunk and upper limbs
What can be done to decrease the “wearing off phenomenon”
increase dose, decrease dosing interval, add COMT inhibitor
What are adverse effects of levodopa
confusion, anxiety, agitation, insomnia, nightmares, depression, psychotic reactions, orthostatic hypotension, nausea, vomiting, anorexia
What drug decreases peripheral metabolism of levodopa by COMT?
COMT inhibitor: entacapone
What does entacapone do in terms of levodopa effects?
smoother response, more prolonged “on” time
What are adverse effects related to with entacapone treatment?
adverse effects are related to increased plasma L-DOPA
What class of monoamine oxidase enzymes do we target with MAOIs. What does it do? What is an example?
MAO-B, which primarily metabolized dopamine. Selegiline
When is treatment with MAOIs useful?
effective early in PD as monotherapy or combined with L-DOPA
what is the benefit of using a dopamine receptor agonist?
bypasses the conversion of L-DOPA to dopamine
What are the adverse effects of dopamine receptor agonists? What helps to lower these effects?
response fluctuations, dyskinesia, lower with L-DOPA therapy
What are examples of dopamine receptor agonists?
Pramipexole, ropinirole
T/F: muscarinic antagonists be used to treat PD? Example?
True; atropine
What is the known mechanism of amantadine (symmetrel)
antiviral; NMDA receptor antagonist, decrease release/reuptake of dopamine, antimuscarinic
What are adverse effects of amantadine (symmetrel)?
agitation, confusion, excitement, restlessness, insomnia, halucinations
What are surgical interventions of PD?
pallidotomy- alleviates akinesia, rigidity, and drug-induced dyskinesia; thalamotomy- ameliorates tremor
What are symptoms of Huntington’s disease?
Hyperkinetic disorder; uncontrolled rapid, jerky movements
What is the etiologic mechanism of Huntington’s disease?
degeneration of striatal neurons projecting to GPe; leads to: increased GPe activity (GABA), decreased STN nucleus activity (glutamate), decreased GPi activity (GABA), loss of thalamic inhibition, increased thalamic excitatory drive
What are the genetic problems of Huntington’s?
expanded CAG (polyglutamine) repeats in huntington gene, autosomal dominant neuronal degeneration resulting in death in 10-20 years
