Ph- Drugs for Movement Disorders Flashcards
What drugs are used to increase dopamine bioavailability?
- levodopa
2. carbidopa
What drugs are used as dopamine receptor agonists?
- pramipexole
2. ropinirole
What are the monoamine oxidase B inhibitors?
- selegiline
2. rasagiline
What is the catechol-O-methyl transferase [COMT] inhibitor?
- entacapone
What are the anticholinergic agents used in the treatment of movement disorders?
- benztropine
2. diphenhydramine
What antiviral drug is also used to treat PD?
- amantadine
What drugs are used to treat spasticity?
- benzodiazopine [GABA agonist]
- baclofen
- dantrolene
____________ is characterized by resting tremor, bradykinesia, rigidity.
_______________ is characterized by hyperkinetic symptoms, especially chorea.
_______________ is characterized by jerky, uncontrolled movements primarily of the face and limbs and is usually the result of use of antipsychotic medications.
Parkinson disease = resting tremor, bradykinesia, rigidity
Huntington’s disease = chorea, hyperkinesia
Dyskinesia [tardive dyskinesia] = jerky movements of the face and limbs
What are the pyramidal and extrapyramidal systems for movement?
Pyramidal = UMN system that controls movement via primary motor cortex–> corticospinal tracts
Extrapyramidal = brainstem, thalamus, cortex, dentate gyrus of cerebellum
What is considered to be the principle relay station of the basal ganglia? Why?
Striatum [caudate and putamen] is the principle relay center of the basal ganglia because it:
- receives input from the cerebral cortex and substantia nigra
- projects output to the 2 globus pallidus segments [external and internal] which transmit signal to the thalamus and back to the cortex
What is the difference in structure between D1 and D2 receptors? What does this mean for action?
D1 is Gs so it increases cAMP and releases more GABA to GPi.
GPi is inhibited so it cannot inhibit the thalamus.
The thalamus signals to the cortex –> movement.
D2 is Gi so it decreases cAMP and releases less Ach. This doesn’t activate the GABA inhibitor of GPe as much.
Increased GPe activity –> increased inhibition of STN.
Less STN stimulus –> less activation of SNr.
Less SNR –> less inhibition of the thalamus leading to increased movement .
The direct motor pathway which involves transmission of _____________ from a striatal neuron to the _________, will do what to the thalamus?
Activation of the indirect pathway, which involves transmission of __________ from a striatal neuron to the __________, will do what to the thalamus?
Direct:
Transmits GABA from striatum –> GPi which will disinhibit the thalamus
Indirect:
Transmission of GABA from striatum –> GPe which will increase the level of inhibition
What is the effect of dopamine on the basal ganglia system?
DA activates the direct pathway [which disinhibits the thalamus] and inactivates the indirect pathway which normally inhibits the thalamus.
The net effect is decreased inhibition of the thalamus which leads to activation of cortical neurons that activate the spinal cord motor neurons.
What is the pathophysiological effect of Parkinson disease on the extrapyramidal system?
Parkinson disease has a progressive loss of pars compacta in the substantia nigra. This leads to less dopamine.
Less dopamine will decrease the direct pathway and increase the effects of the indirect pathway leading to inhibition of the thalamus and decreased activation of cortical neurons for movement
What is the effect of Huntington disease on the basal ganglia?
HD leads to degeneration of the GABA neurons of the indirect pathway.
This leads to decreased inhibition of GPe, which increases inhibition of the STN. There is less activation of SNr and less inhibition of the thalamus leading to excess stimulation of the thalamus .
Why is it possible for anticholinergics to help treat Parkinson disease?
Dopamine usually inhibits the release of Ach from D2 in the indirect pathway.
Ach activates the inhibitor of GPe which will reduce inhibition of STN which will increase activation of SNr and increase inhibition of the thalamus–> decreased movement.
Anticholinergics can be used to “turn off” the indirect pathway to release inhibition of the thalamus and increase movement
What is the rate-limiting step of dopamine synthesis?
What cofactors are required for this step?
Tyrosine– [tyrosine hydroxylase]–> L-dopa
Cofactors necessary: tetrahydropterin, Fe2+
What enzyme converts L-dopa to dopamine?
Where is the enzyme found?
aromatic amino acid decarboxylase {AAAD}
It is found in neuronal cytoplasm, but also has a broad tissue distribution in the periphery
*this explains why a lot of ingested L-Dopa is converted to dopamine in the periphery
Dopamine is transported into synaptic vesicles by a transport protein that is inhibited by ___________.
Reserpine
Describe what happens when dopaminergic neurons are stimulated.
- intracellular free Ca rises and dopamine is released by exocytosis
- most of the released dopamine is taken back up by its selective transporter, DAT
- the dopamine that is not taken back up is metabolized by COMT, or is oxidized by MAO-B
