Pharmacology Movement disorder - Parkinson Dr. Pond Flashcards
Characteristics of Parkinson
Combination of
-ridigity
-brdaykenisia
-resting tremor (when they are at rest)
-postural instability
Which group of structures controls the body’s ability to move?
Basal ganglia
What are the structures within the Basal ganglia
-Striatum:
caudate nucleus
putamen
-globus pallidus
internal and external part
-subthalamic nucleus (nucleus right below the thalamus)
-the substantia nigra
reticular part (SNr)
compact part )SNc)
What is the relation between the substantia nigra and the striatum?
The axon terminal of dopamine neurons of the substantia nigra (pigmented) project to the striatum
Motor function ->the death of these neurons results in PD!
Nigrostriatal pathway: substantial nigra to caudate-putanem
Which abilities are affected by the impairement of the mesolimbic and mesocortical pathways?
Memory
Motivation
Reward and desire
Addiction
Cognition
Which pathway regulates the release of prolactin?
Dopmain release in the Tuberoinfundibular pathway
Which dopamine receptors are involved in the Nigrostriatal pathway?
D1 receptor: excitatory (increasing cAMP)
D2 receptor: inhibitory (decrases cAMP)
Which of the D receptors facilitates or inhibits movement?
D1 receptor: facilitates movement -> direct pathway (inhibits an inhibitory neuron by activating GABA)
D2 receptor: inhibits movement -> indirect pathway
->if the dopamine release from the substantial nigra is impaired -> we lose the stimulatory and inhibotry pathways -> missregulation of movement in PD (bradykaneisa)
Benefit of Sinemet
Sinemet (L-Dopa + Carbidopa)
L-Dopa is converted to Dopamine via the dopa decarboxylase (causing side effects in the periphery)
Carbidopa is a peripheral dopa decarboxylase inhibitor -> so less L-Dopa will be present in the peripheral (toxic) -> we can give a lower dose with Sinemet
Why don’t we use Dopamine as a drug?
It doesnt cross the BBB
L-Dopa does
ADE of peripheral toxictiy of L-Dopa
-orthostatic hypotension
-arrhythmias
-nausea and vomiting
Other ADEs of L-Dopa
Psychotic disorder: Anxiety, agitation, insomnia, hallucinations, delusions, nightmares, mood changes
-dyskinesias (too much dopamine in the nigrostatial pathway)
-compulsive behavior
What is a significant side effect we see after long-term use of L-dopa/carbidopa
Wear-off effect
-predictable fluctuation of motor function
-> Increase frequency of dosing
What represents the end-stage of L-Dopa therapy
On-Off phenomen
-severe, unpredictable fluctuations in motor function
-> Normal function (on) and akinesia/bradykinesia (off)
-> dyskinesia (involuntary movements) during on-period
What is the susbtrate and product of COMT?
COMT converts L-Dopa (substrate) to 3-O-methyldopa
-since the dopa-decarboxlyase is inhibited with L-dopa/carbidopa -> there is more L-dopa available -> the body compensates by increasing the peripheral COMT activity
Which drug is known to be a COMT-inhibitor?
-Tolcapone
-opicapone
-entacapone
doubles the half-life of L-Dopa -> more access to CNS
->limits fluctuation in L-Dopa
Which of the COMT inhibtors dont cross the BBB?
opicapone
entacapone
Which drug contains levodopa + carbidopa + entacapone and what is its side effect?
-Stalevo
-higher risk of dyskinisia
-also nausea, confusion, diarrhea, fatigue, drowsiness, hallucinations
-discoloration of urine - may be seen with levodopa
Which receptors contribute to the indirect “STOP” pathway inhibiting movement controlled by the motor cortex?
Adenosine receptors (A(2A))
Which drug is used to combat higher levels of adenosine receptors in the basal ganglia?
-Istradefylline (Adenosine receptor antagonist)
ADE: Dyskinesias; constipation and nausea;
dizziness, insomnia; abnormal behaviors, hallucinations,
delusions, impulse control disorder
What is the role of Monoamine oxidase and MOA-inhibitors?
Monoamine oxidase causes intracellular degradation of Monoamines
MOA-A: degrade NE and 5-HT
MOA-B: degrades Dopamine
MOA-B inhibitor: will increase the level of dopamine in the neuron -> recycled -> counteracts the PD
Cheese effect DDI with MAO-inhibitors
hypertensive crisis resulting from interaction
with sympathomimetic agents
-> less seen with MAO-B inhibitors
DDI with MAO inhibitors - Serotonin syndrome
Caution when using: SSRIs, TCA, other MAO inhibitors
hyperthermia, rigidity, myoclonus (muscle jerks),
mental and vital sign changes, seizures, coma with 5-HT drugs
DDI with MAO inhibitors and Dextromethorphan
psychosis, bizarre behavior
DDI with MAO inhibitors and opioids
potentiate CNS/respiratory depression
Which drug is a reversible MAO-B inhibitor?
-Safinamide
-Add on treatment for patients experiencing “off” episodes
MOA Dopamine agonists
-mimics the effect of dopamine
-Pramipexole (D3 agonist)
-Ropinirole (D2 agonist)
-Rotigotine (D3, D2, D1 agonist)
-> newer agents with less side effects
-Apomorphine - helpful in “off-periods”
Muscarinic receptor antagonists
-Benztropine
-trihexyphenidyl
ACh neuron causing overaction of the GABA neuron in the nigrostriatal pathway
-> blocking the muscarinic receptor
treats the tremor and rigidity better than bradykinesia
ADE: dry mouth, flush, increased heart rate, dilated pupils, constipation, urinary retention, delirium
MOA of Amantadine
not fully understood
-influences levels of dopamine in the synapsis
-may increase D2 receptor expression
What determines if someone carries Huntington’s disease?
more than 36 glutamine residues on a gene on the Chromosome 4
-> production of an abnormal protein
Which structures of the brain are involevd in Huntington’s disease?
degeneartion of neurons within
-striatum (movement) -> dyskinesia (chorea - dance uncontrolled)
-cortex (thought, perception, memory)
MOA of Reserpine and tetrabenazine
in the disease, GABA neurons are degenerated
-> so we want to inhibit dopamine neurons that inhibit the remaining GABA neurons
-depletion of dopamine and other monoamines by preventing interneural storage - blocking vMAT -> so dopamine doesn’t get into vesicles but stays in the cytosol -> and will be degraded by MAO-B (mitochondria)
-may also use dopamine receptor antagonists or BZ
What is the BBW for tetrabenazine?
Depression and suicidal thoughts
-> since all monoamides (dopamine, NE, serotonin) are depleted it causes severe depression, may also cause Parkinson due depleting dopamine
Drugs indicated for Restless leg syndrome
-dopamine agonists: Ropinirole, Rotigotine
-levadopa
-GABA enhancing drugs
-Gabapentin
-opioids
-iron supplementation may work - there is a link between patients with iron deficiency and anemia and having the symptomes
