1. Antiparkinson Drugs Flashcards
A Parkinson patient enters your dental office with:
• severe motor disturbances
• ____ of the hands
• random muscle activity
• ____ (drooling) from disease or xerostomia from drugs
• difficulty complying with your needs
• Prescribed ____, Dopamine Agonists, antimuscarinics, MAO and COMT inhibitors
• potential for drug:drug interactions
tremors
sialorrhea
L-DOPA
The basic problem in Parkinsonism: • a progressive neurodegenerative disorder • imbalance of \_\_\_\_ • especially in the \_\_\_\_ • \_\_\_\_ has a critical role
CNS neurotransmitters
basal ganglia
dopamine
Major symptoms of Parkinsonism
• ____ (difficulty in starting a movement; basically a locomotion disorder)
• ____ (slow gait; shuffles)
• ____ at rest; “pill rolling”
• muscle ____; mask-like facial expression
• ____
akinesia
bradykinesia
tremor
rigidity
More historical highlights
• anticholinergics for excessive ____; tremor improves.
• animal studies show high concentrations of dopamine in the ____.
• autopsies of Parkinson patients show depletion of dopamine in cells of the ____.
• the ____ are implicated
• dopamine ____ is not effective
• ____ provides transient remission.
salivation basal ganglia substantia nigra basal ganglia administration L-dopa
The basal ganglia are comprised of five subcortical nuclei (clusters of neurons): – \_\_\_\_ (caudate + putamen) – \_\_\_\_, external segment – \_\_\_\_, internal segment – \_\_\_\_ – \_\_\_\_
striate cortex globus pallidus globus pallidus substantia nigra subthalamic nucleus
• To review, blue oval is the caudate nucleus and the putamen
• Other blue circle is the globus pallidus
• Orange- thalamus. This is like the ____ part of our brain. By the way, when we
did some of our brain scanning studies on analgesics effects. One of the things we consistently saw (and we don’t know if it’s a mechanism of the drug or not) but not only did cerebral blood flow in the thalamus DECREASE, but it ____. We would see pts after 3rd molar pain, the right side would be hotter than the left side. Blood flow correlates very closely with neuroactivity. Then when they got pain relief, blood flow ____ and now right and left had the same amount of blood flow.
• Red- Substantia nigra. This is where most of the ____ is getting depleted.
• POINTS TO LOCUS COERULEUS and DORSAL RAPHE NUCLEUS- which are important in ____ pathways. So pathways from there actually descend and go from central to more peripheral. They turn off the release of ____ and excitatory amino acids in the dorsal Horn of the spinal cord and the medulla. These are sort of like analgesic pathways. We think opioids stimulate these.
primitive normalized diminished dopamine descending analgesic substance p
Causes of parkinsonism
____…causes unknown
____ disease…such as flu iatrogenic…as with ____ neurotoxin…as with ____
MPTP provides a breakthrough in cause of PD, as well as in its treatment
idiopathic
postencephalic
halperidol
MPTP
- This MPTP, this was the contaminate. (Its full name is on the slide.)
- MPTP readily crossed the ____, and readily got into neurons. Very lipophilic. But in the neurons, there was ____. This is inside the neuronal cytoplasm.
- MAO-A is a predominantly the MAO that you find in the periphery but it’s not like absolute.
- once this contaminant crossed into the neuron→ because of this interaction by MAO-B it got converted to ____. (What do you know about charge vs. charge molecules, as far as getting in and out of things? Charged species get ____. Ex: local anesthetics when you inject at a low pH & inflammation it’s tough to get him numb. why? because the molecules charged, it has a hard time penetrating the nerve.) This is kind of the opposite it → it penetrates and now it cannot get ____. This (points to the red circle on MPP+) targets the mitochondria and kills the neuronal cell. It is very selective for neuronal cells that contain ____.
BBB MAO-B MPP+ trapped out dopamine
Pharmacology of MPTP
- MPTP penetrates the ____ neurons in the SN
- biotransformed into ____
- charged molecule unable to exit cell
- attacks the ____
- disturbs the “powerhouse”
- cells degenerate
doapminergic
MPP+
mitochondria
A synthetic neurotoxin
- They developed animal models of this MPTP stuff. They gave rodents MPTP and the rodents got Parkinson’s disease. A rat with Parkinson’s disease.
- if you pretreated the animals with an ____, Selegiline, they DID NOT get it! because why? the MPTP couldn’t get converted to ____
- probably the major benefit of MAO-B Inhibitors in Parkinson’s is that -one of the ways that dopamine is degraded is by MAO. so it increases ____ levels in the central nervous system.
- by the way eventually these drugs are not going to work. why? because as Parkinson’s progresses, you will eventually have no ____ left. That’s why I-dopa went is sometimes only good for about 7-8 yrs, bc the nerve terminals that you need to contain the dopamine are not there anymore.
• But at least for now we think a lot of the activity of these drugs is blocking dopamine metabolism
MAO inhibitor
MPP+
dopamine
dopamine
Simplified View of Motor Neurophysiology
• There is dopaminergic input from the ____ that is key.
• maybe what’s going on is that this dopamine is acting as a brake on the production of
acetylcholine
• if this (points to dopamine) gets knocked out then there’s no ____ and there’s an
alternate pathway where ____ can be formed.
- you can see from this schematic (and I don’t want to get into what every one of these things are doing), you can see that ____ is involved (going to speak a lot about GABA when we speak about benzodiazepines)
- and to make things even more complex, there’s a direct pathway from the striatum to the motor cortex where it seems to be the key neurotransmitter is ____.
- Again, things that interact w/ glutamate and GABA does not seem to clinically ____ those w/ Parkinson’s disease
substantia nigra
dopamine
acetylcholine
GABA
glutamate
help
The ____ is the major focus in Parkinson’s disease
substantia nigra
Transmitters in the basal ganglia • \_\_\_\_ • \_\_\_\_ • \_\_\_\_ • \_\_\_\_
dopamine
acetylcholine
gamma amino butyric acid
glutamate
The transmitter DA can produce different actions on the same neural structure by ____ at DA receptor ____.
selective actions
subtypes
Dopamine receptor nomenclature
- Family
- D
- Sub-family
- D1 and D2
- Receptor sub-types
- D(1) D(2) D(3) D(4) D(5)
• you can have a ____ of dopamine, this is kind of like your relatives → D (dopamine) receptor
• There are ____, this is like the children —> D1 & D2 receptors (we think the we think the benefit of most of the dopamine stimulating anti-Parkinson drugs are on the ____ receptor)
• receptor sub-types—> D1, D2, D3, D4, D5
◦ *D2→ D2, D3, D4
◦ *D1→ D1, D5
family
sub-family
D2
In the caudate-putamen, the D2 receptor subtype is ____ and the D1 receptor subtype is ____.
inhibitory
excitatory
In Parkinson’s disease: we are very heavy on the ____ and we’re very light on the ____. That that pretty much tells you how to treat the disease
acetylcholine
dopamine
