ICL 5.0: Pharmacology of Neurodegenerative Disease Flashcards
what is the direct pathway involving the basal ganglia?
DIRECT PATHWAY:
cortex –> striatum –> globus pallidus internus and substantia nigra –> thalamus –> cortex
so the cortex releases glutamate which activates the striatum –> then the putamen synapses in the globus pallidus internus and releases inhibitory GABA
the globus pallidus neurons usually go to the thalamus and release GABA to inhibit the thalamus but since the globus pallidus is being inhibited by the putamen, the thalamic neurons are now active! the thalamus then goes and activates the motor cortex so that it can go and initiate movement
the direct pathway initiates movement!
what is the indirect pathway involving the basal ganglion?
INDIRECT PATHWAY:
cortex –> striatum/putamen –> globus pallidus externus –> subthalamic nucleus –> globus pallidus internal –> thalamus –> cortex
so the cortex is stimulating the putamen by releasing glutamate and then the neurons from the putamen synapse in the globus pallidus externus and release GABA to inhibit the GPE –> the GPE then normally inhibits the subthalamus but since the GPE is inhibited, the subthalamus is activated and it goes and releases glutamate to activate the globus pallidus internus
the globus pallidus internus is inhibitory so it will go and release GABA and inhibit the thalamus so the thalamus no longer stimulates the cortex to produce movement
so the indirect pathway stops movement!
striatum = caudate nucleus + putamen
how does the substantia nigra effect the direct and indirect pathways normally?
the direct pathway is used to initiate movement while the indirect pathway is used to inhibit movement so together they work together to allow for proper movement!
the substantia nigra has dopaminergic neurons that synapse in the putamen either on the D1 receptors of the direct pathway neurons or on the D2 receptors of the indirect pathway neurons –> D1 receptors activate a stimulatory pathway while D2 receptors activate an inhibitory pathway
so dopamine binding to D1 receptors provides more intense action potentials in the direct pathway and allows for even more movement! but if dopamine binds to the D2 receptors in the indirect pathway and inhibits them, you stimulate the primary motor cortex! so dopamine is trying to enhance motor movement overall!
when you want to flex your biceps, you have to activate the biceps and inhibit the triceps –> in Parkinson’s, if there’s alternating contraction and relaxation that’s how you get tremors! also if there’s constant contraction through the direct pathway, that’s what gives you the rigidity!!
how do cholinergic neurons play a role in the effect of dopamine on the direct and indirect pathway?
dopamine normally activates the direct pathway and inhibits the indirect pathway in the putamen of the basal ganglia
the cholinergic neurons in the putamen do the exact opposite effect of dopamine –> so cholinergic neurons stimulate the indirect pathway and inhibit the direct pathway in the putamen
what happens to the neuroanatomy of the basal ganglia involved in motor function in a Parkinson’s patient?
there is degeneration of the dopaminergic neurons in the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway = lots of inhibition of movement!
without dopamine being released on the D1 receptors of the direct pathway and the D2 receptors of the indirect pathway, the direct pathway won’t be activated as much and indirect pathway won’t be inhibited as much which leads to overactivity of the indirect pathway! this is why Parkinson’s patients have such a hard time contracting their muscles = akinesia/bradykinesia!!! this is why they have a shuffling gait because they can’t get their muscles to go but it’s also why sometimes they have the march a petit where their walker ends up really ahead of them because they also can’t stop the movement once they get going because that also requires muscles!
loss of the inhibitory effect of dopamine results in more production of Ach which triggers a chain of abnormal signaling leading to impaired mobility
there is also aggregation of Lewy bodies in the substantia nigra which leads to neuron death of dopaneurgic neurons
what is Parkinson’s disease?
a progressive neurodegenerative disease where there is loss of dopamine neurons in the substantia nigra and the presence of Lewy bodies (eosinophilic cytoplasmic inclusions) in the surviving dopamine neurons
aggregates of the Lewy bodies in the dopaneurgic neurons is what’s killing them
what is the clinical presentation of Parkinson’s disease?
- resting tremor –> pill-rolling tremor
- bradykinesia (slowness)
- rigidity –> cog-wheel rigidity in upper limbs and lead rigidity in lower limbs
- postural instability = impaired balance and hunched back; appears late in the course of the disease
- long term disability includes: worsening motor fluctuations and dyskinesias, dementia
- masked face = doesn’t show emotions
TRAP = tremors, rigidity, akinesia, postural instability
why do Parkinson’s patients have tremors and rigidity?
the cholinergic neurons love to oppose dopamine so they love to inhibit the direct pathway and excite the indirect pathway in the putamen
normally ACh and dopamine are in balance but in Parkinson’s there is a decreased amount of dopamine which increases the effect of the cholinergic neurons – this fluctuation between ACh and dopamine is what causes both tremors and rigidity!
how do you treat Parkinson’s?
you can’t actually treat it….
once the neurons in the substantia nigra die, they can’t be regenerated so you just have to treat the symptoms
what are the 3 primary compounds used to treat Parkinson’s?
- increase dopamine synthesis
- decrease dopamine catabolism
- stimulate dopamine receptors (agonists)
what are the 3 secondary compounds used to treat Parkinson’s?
- antagonize muscarinic cholinergic receptors
- enhance dopamine release
- N-methyl-D-aspartate (NMDA) gluta mate receptors
how is dopamine synthesized?
tyrosine –> L-dihydroxy phenylalanine via tyrosine hydroxylase (TH)
then L-dopa –> dopamine via dopa decarboxylase
what is the MOA of levodopa/carbidopa?
levodopa + carbidopa = Sinemet®
this is used to treat Parkinson’s!
levodopa is the immediate metabolic precursor of dopamine which crosses the blood-brain barrier
however, the problem is that it can be decarboxylated into dopamine!! before it even gets to the brain! so that’s why levodopa is combined with carbidopa because carbidopa is a peripheral dopa-decarboxylase inhibitor so it keeps levodopa in the levodopa form until it gets to the brain where it can be decarboxylated into dopamine
if you give levodopa by itself, only 1-3% wlll get to the brain whereas when it’s combined with carbidopa 10% will get to the brain
should you take levodopa with or without food?
Levodopa should be taken on an empty stomach
ingestion of meals containing high protein content interferes with the transport of levodopa
what are the adverse effects of levodopa if it’s given alone with carbidopa?
- GI distress = anorexia, nausea, vomitting
- cardiac arrhythmias
- hallucinations
- dyskinesias
- motor fluctuations
when you give levodopa with carbidopa you reduce its metabolism in the peripheral tissues and GI tract which decreases the side effects
what drug interactions does levodopa have?
pyridoxine (vitamine B6) enhances the extracerebral metabolism of levodopa
so patients are told to avoid vitamin B6 since it promotes the metabolism of levodopa in the periphery
what is the MOA of entacapone?
aka Comtan®
entacapone is a peripherally acting inhibitor of catechol-O-methyltransferase (COMT)
when peripheral dopamine decarboxylase activity is inhibited by carbidopa a significant concentration of 3-O-methyldopa is formed via COMT –> 3-O-methyldopa competes with levodopa for active transport into the CNS
inhibition of COMT by entacapone leads to decrease concentration of 3-O-methyldopa which increases the central uptake of levodopa = more dopamine in the brain
entacapone prolongs the action of levodopa by diminishing its metabolism
used to treat Parkinson’s
what is the MOA of tolcapone?
it’s a central AND peripheral inhibitor of COMT
when peripheral dopamine decarboxylase activity is inhibited by carbidopa a significant concentration of 3-O-methyldopa is formed via COMT –> 3-O-methyldopa competes with levodopa for active transport into the CN
inhibition of COMT by tolcapone leads to decrease concentration of 3-O-methyldopa which increases the central uptake of levodopa = more dopamine in the brain
used to treat Parkinson’s
what are the adverse effects of tolcapone and entacapone?
COMT inhibitors increase levodopa availability and consequently cause:
- dyskinesias
- nausea
- confusion
- abdominal pain
- sleep disturbances
- orange discoloration of the urine
**tolcapone is related to hepatotoxicity so it’s not prescribed often
what is Stalevo?
a commercial preparation composed of Entacapone/Levodopa/Carbidopa
used to treat Parkinson’s
what is the MOA of selegiline?
aka Deprenyl®
selegiline is a selective inhibitor of monoamine oxidase B (MAO-B) which metabolizes dopamine in the CNS
so selegiline enhances and prolongs the antiparkinsonism effect of levodopa (so it’s given as a booster of Sinemet)
what do you have to be cautious of when dosing selegiline?
- at higher doses, selegiline can also inhibit MOA-A too though which isn’t good because you could cause serotonin syndrome due to a build up of serotonin so you have to have a balanced dose
serotonin syndrome triad = confusion, fever and myoclonus (involuntary muscle jerk)
- “cheese effect”
hypertensive crisis – certain foods like cheese, wine and meat are high in tyramine and MAO inhibitors like selegiline block the breakdown of tyramine and high levels of tyramine cause hypertension
what are some of the adverse effects of selegiline?
- insomnia and excessive daytime sleepiness
- mood changes
- dyskinesias
- GI distress
- hypotension
