Term
| what is a neurodegenerative disorder? |
|
Definition
| progressive and irreversible loss of neurons from specific areas of the brain |
|
|
Term
| what is the most common type of NDD that will be treated? |
|
Definition
|
|
Term
parkinson's disease
region of brain affected?
clinical symptoms?
frequency? |
|
Definition
basal ganglia
movement disorder
1% >65 years old |
|
|
Term
progressive supranuclear palsy
region of brain affected?
clinical symptoms?
frequency? |
|
Definition
basal ganglia
movement disorder tremors
less common than PD |
|
|
Term
dystonia
region of brain affected?
clinical symptoms?
frequency? |
|
Definition
basal ganglia
movement disorder
inherited; relatively rare |
|
|
Term
| which NDD is easiest to treat? |
|
Definition
|
|
Term
Huntington's Disease
region of brain affected?
clinical symptoms?
frequency? |
|
Definition
basal ganglia
movement disorder
inherited; relatively rare |
|
|
Term
alzheimer's disease
region of brain affected?
clinical symptoms?
frequency? |
|
Definition
hippocampal and cortical neurons
impairment of memory and cognitive ability
10% >65 years old |
|
|
Term
amyotrophic lateral sclerosis (ALS)
region of brain affected?
clinical symptoms?
frequency? |
|
Definition
spinal, bulbar and cortical motor neurons
muscular weakness
relatively rare |
|
|
Term
| currently available therapy for NDD is limited to what? |
|
Definition
|
|
Term
| what 2 NDD is therapy relatively effective for? |
|
Definition
1. PD
2. inherited dystonia |
|
|
Term
| is therapy for NDD curative? |
|
Definition
| NO it can only alleviate symptoms for a certain amount of time |
|
|
Term
| clinical symptoms of PD (4)? |
|
Definition
1. bradykinesia - slowness of movement
2. muscular rigidity
3. resting tremor
4. impairment of postural balance |
|
|
Term
| what may be an initial symptom of PD? |
|
Definition
difficulty in performing simple manual function
tremor of one hand |
|
|
Term
| PD tremor often improves with what? |
|
Definition
|
|
Term
| what is seen in stage 4 PD? |
|
Definition
| significant disability - limited ambulation with assistance |
|
|
Term
| what is seen in stage 5 PD? |
|
Definition
complete invalidism - patient confined to bed or chair
can't stand or walk even with assistance |
|
|
Term
|
Definition
80-90% loss of pigmented dopaminergic neurons of the substantia nigra pars compacta
80% reduction in striatal dopamine content |
|
|
Term
| what causes the problems in PD? |
|
Definition
|
|
Term
| what happens to the substantia nigra in PD? |
|
Definition
| 80% or more is de-pigmented |
|
|
Term
| what areas of the brain have the most DA normally? |
|
Definition
| putamen, caudate, substantia nigra |
|
|
Term
| what is the normal degradation product of DA? |
|
Definition
|
|
Term
| how do the levels of DA and homovanillic acid change in PD? |
|
Definition
| both are decreased because there is no DA to be broken down |
|
|
Term
| how do the levels of DA and homovanillic acid change with L-dopa treatment in a PD patient? |
|
Definition
both increase
hard to treat without over-correcting the breakdown product --> cause of side effects |
|
|
Term
| synthesis of DA is from what amino acid? |
|
Definition
|
|
Term
what enzyme converts tyrosine to dopa?
what is the co-factor for this reaction? |
|
Definition
tyrosine hydroxylase
tetrahydrobiopterin
this is the slow reaction of DA biosynthesis |
|
|
Term
what enzyme converts dopa to dopamine?
what is the co-factor for this reaction? |
|
Definition
dopa decarboxylase
pyridoxal phosphate
this is the fast reaction of DA biosynthesis |
|
|
Term
| how does the D1 receptor family work? |
|
Definition
| increases cAMP --> increase PIP2 hydrolysis --> Ca mobilization --> PKC activation |
|
|
Term
| how does the D2 receptor family work? |
|
Definition
| decrease cAMP --> increase K currents --> decrease voltage gated Ca currents |
|
|
Term
| what 2 receptors are in the D1 family? |
|
Definition
|
|
Term
| what 3 receptors are in the D2 receptor family? |
|
Definition
|
|
Term
| what DA receptors are located in the striatum and substantia nigra? |
|
Definition
|
|
Term
| what is the aim of all classes of drugs to treat PD? |
|
Definition
| to increase DA or DA action in the synaptic cleft |
|
|
Term
| classes of drugs to treat PD (6)? |
|
Definition
1. DA precursor
2. inhibitors of peripheral COMT
3. inhibitors of central MAO
4. DA receptor agonists
5. Ach receptor antagonists
6. amantadine - DA release |
|
|
Term
| how does levodopa work to treat PD? |
|
Definition
| increases synthesis of DA in the brain by administration of its precursor L-dopa |
|
|
Term
| enzyme that converts levodopa to dopamine? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| a peripherally acting inhibitor of dopa decarboxylase |
|
|
Term
| why is carbidopa administered with levodopa? |
|
Definition
| it allows levodopa to reach the brain before it is converted to DA |
|
|
Term
| what are the 2 most important adverse effects of levodopa/carbidopa? |
|
Definition
1. primarily excessive and abnormal involuntary movements (dyskinesia) - 75%
2. on/off phenomenon |
|
|
Term
| what is the on/off phenomenon of levodopa/carbidopa treatment? |
|
Definition
| rapid fluctuation between on (responding to treatment but with disabling dyskinesia) and off (no beneficial effect) |
|
|
Term
| what happens in 2-5 years of treatment with levodopa/carbidopa? |
|
Definition
| beneficial effects of treatment wear off and are outweighed by adverse side effects |
|
|
Term
| when should treatment of PD be initiated? |
|
Definition
| only when symptoms cause functional impairment |
|
|
Term
| what is used in an attempt to minimize the on/off phenomenon of levodopa/carbidopa? |
|
Definition
| a sustained release form of the drug |
|
|
Term
| what are other adverse effects of levodopa/carbidopa? |
|
Definition
1. nausea and vomiting - 40-50%
2. orthostatic hypotension - 25-30%
3. cardiac arrhythmia
4. abrupt withdrawal may cause neuroleptic malignant syndrome - rare
5. hallucinations and confusion - 25% |
|
|
Term
| what can happen with abrupt withdrawal of levodopa/carbidopa? |
|
Definition
| neuroleptic malignant syndrome |
|
|
Term
| what is neuroleptic malignant syndrome? |
|
Definition
very sudden increase in temp and rigidity
can cause resp distress and collapse |
|
|
Term
| how do you treat hallucination and confusion side effects of levodopa/carbidopa? |
|
Definition
antipsychotics
eg. phenathiazines, clozapine |
|
|
Term
| what should be discontinued at least 14 days before initiation of levodopa/carbidopa therapy? |
|
Definition
| non-specific MAOIs which act on MAO-A (an isoform predominately in the periphery) |
|
|
Term
| why should non-specific MAOIs be discontinued before initiation of levodopa/carbidopa therapy? |
|
Definition
| to avoid HTN crisis and hyperpyrexia |
|
|
Term
| how long before initiation of levodopa/carbidopa therapy should non-specific MAOIs be discontinued to avoid HTN crisis and hyperpyrexia? |
|
Definition
|
|
Term
| how do inhibitors of peripheral COMT work to treat PD? |
|
Definition
| inhibition of peripheral COMT prolongs the effectiveness of DOPA by increasing the amount that reaches the brain |
|
|
Term
| what are 2 inhibitors of peripheral COMT used in treatment of PD? |
|
Definition
1. tolcapone
2. entacapone |
|
|
Term
| what has to be monitored when using tolcapone? |
|
Definition
| liver enzymes because hepatotoxicity may occur |
|
|
Term
| how does entacapone differ from tolcapone? |
|
Definition
| no hepatotoxicity has been reported |
|
|
Term
| side effects of tolcapone? |
|
Definition
|
|
Term
| what are tolcapone and entacapone approved for? |
|
Definition
| adjunctive use with levodopa/carbidopa |
|
|
Term
| how do levodopa/carbidopa + peripheral COMT inhibitors work to treat PD? |
|
Definition
| facilitate entry of DOPA into the brain where it is converted to DA by DOPA decarboxylase |
|
|
Term
| how are inhibitors of MAO used to treat PD? |
|
Definition
| used to slow down the degradation of DA in the brain |
|
|
Term
| how do centrally acting MAOIs act in treating PD? |
|
Definition
| stop DA from being degraded once it gets in the brain |
|
|
Term
| what 2 MAOIs are used in treatment of PD? |
|
Definition
1. selegiline
2. rasagiline |
|
|
Term
| what is the predominant isoform of MAO in the striatum? |
|
Definition
|
|
Term
| how do selegiline and rasagiline act in treatment of PD? |
|
Definition
selectively and irreversibly inhibit MAO-B (the predominant isoform of MAO in the striatum)
decrease the rate of DA degradation in the striatum |
|
|
Term
|
Definition
| useful in patients with early or mild PD |
|
|
Term
| adverse effects of selegiline? |
|
Definition
1. in advanced PD - may accentuate adverse effect of levodopa therapy
2. metabolized to amphetamine and methamphetamine which may cause anxiety, insomnia, and other adverse symptoms |
|
|
Term
| what is a potential adverse effect of selegiline in advanced PD? |
|
Definition
| it may accentuate adverse effect of levodopa therapy |
|
|
Term
| how can selegiline cause anxiety and insomnia? |
|
Definition
| its metabolized to amphetamine and methamphetamine |
|
|
Term
| how does rasagiline differ from selegiline? |
|
Definition
| its not metabolized to amphetamine |
|
|
Term
| when is rasagiline effective in PD treatment? |
|
Definition
| effective and well-tolerated in early and late PD |
|
|
Term
| what 2 older drugs act as DA receptor agonists for treatment of PD? |
|
Definition
| pergolide and bromocriptine |
|
|
Term
| how do pergolide and bromocriptine act in treatment of PD? |
|
Definition
| act as DA receptor agonists directly on D1 and D2 DA receptors |
|
|
Term
| pergolide and bromocriptine are both what? |
|
Definition
|
|
Term
| pergolide and bromocriptine administration? |
|
Definition
|
|
Term
| half life of pergolide and bromocriptine? |
|
Definition
|
|
Term
| how does the duration of action of pergolide and bromocriptine compare to levodopa? and why is this important? |
|
Definition
it is longer
gives less on/off fluctuation |
|
|
Term
| why must pergolide and bromocriptine be initiated at low doses and slowly adjusted upwards? |
|
Definition
|
|
Term
| what must you do with pergolide and bromocriptine in order to avoid hypotension? |
|
Definition
| initiate at low dosage and slowly adjust upwards |
|
|
Term
| what is the most common use of pergolide and bromocriptine? |
|
Definition
| in combo with levodopa/carbidopa in advanced PD |
|
|
Term
| adverse effects of pergolide and bromocriptine? |
|
Definition
1. dyskinesias
2. orthostatic hypotension
3. hallucinations and confusion
4. pleuropulmonary and retroperitoneal fibrosis
5. erythromelalgia and digital vasospasm due to ergot |
|
|
Term
| what are 2 newer DA receptor agonists used in the treatment of PD? |
|
Definition
1. ropinirole
2. pramipexole |
|
|
Term
| how do ropinirole and pramipexole work in treatment of PD? |
|
Definition
| bind selectively to D2 receptors |
|
|
Term
| ropinirole and pramipexole use? |
|
Definition
in early PD without levodopa
in advanced PD with levodopa |
|
|
Term
| when ropinirole and pramipexole are used in advanced PD what has to be added? |
|
Definition
|
|
Term
| why do ropinirole and pramipexole have less adverse side effects than pergolide and bromocriptine? |
|
Definition
| they are not ergot derivatives |
|
|
Term
| what is a long lasting DA receptor agonist? |
|
Definition
|
|
Term
| what receptors do cabergoline work on? |
|
Definition
| high affinity for D2 receptors |
|
|
Term
| cabergoline is approved for use in treatment of what? |
|
Definition
hyperprolactinemia
investigational for use in treatment of PD |
|
|
Term
| what is the effect of Ach receptors on striatal neurons? |
|
Definition
exert an excitatory effect opposite of DA
also exert a presynaptic inhibitory effect on DA nerve terminals |
|
|
Term
| how are Ach receptors used in treatment of PD? |
|
Definition
| suppression of Ach receptors (by antagonists) makes up, in part, for the lack of DA |
|
|
Term
| why do Ach antagonists have effectiveness in treating PD? |
|
Definition
because the balance between Ach and DA is what is important
therefore, decrease Ach changes the balance and has similar effects to increasing DA |
|
|
Term
| what 3 Ach receptor antagonists are used in the treatment of early PD? |
|
Definition
1. trihexyphenidyl
2. benztropine mesylate
3. diphenhydramine |
|
|
Term
| trihexyphenidyl, benztropine mesylate, and diphenhydramine use? |
|
Definition
| as an adjunct to levodopa/carbidopa in treatment of early PD |
|
|
Term
| where do trihexyphenidyl, benztropine mesylate, and diphenhydramine act? |
|
Definition
| at cholinergic striatal interneurons |
|
|
Term
| how many subtypes of Ach receptors are found in the striatum? |
|
Definition
|
|
Term
| what are adverse effect of Ach receptor antagonist due to? |
|
Definition
| their anti-cholinergic properties |
|
|
Term
| adverse effect of Ach receptor antagonists (8)? |
|
Definition
1. mydriasis
2. cycloplegia
3. urinary retention
4. decreased GI motility
5. tachycardia
6. dry mouth
7. memory impairment
8. delirium (in high doses) |
|
|
Term
| mechanism of action of amantadine? |
|
Definition
no clear
may be on DA release and/or re-uptake or on NMDA receptors |
|
|
Term
|
Definition
initial therapy of mild PD
as an adjunct to DOPA/carbidopa in more advanced PD |
|
|
Term
| adverse side effects of amantadine? |
|
Definition
| less severe than with other PD drugs |
|
|
Term
| what are 3 surgical procedures for treatment of PD? |
|
Definition
1. fetal mesencephalic tissue implant
2. surgical intervention - thalamotomy, pallidotomy
3. deep brain electrical stimulation |
|
|
Term
| fetal mesencephalic tissue implant treatment of PD shows improvement in what? |
|
Definition
on/off phenomenon
bradykinesia
rigidity |
|
|
Term
| fetal mesencephalic tissue implant treatment of PD does not show improvement in what? |
|
Definition
|
|
Term
| what may be needed with fetal mesencephalic tissue implant treatment of PD? |
|
Definition
|
|
Term
| thalamotomy or pallidotomy treatment of PD needs to be ____ |
|
Definition
| done on both sides of the brain |
|
|
Term
| thalamotomy treatment of PD shows improvement in what? |
|
Definition
|
|
Term
| pallidotomy treatment of PD shows improvement in what? |
|
Definition
rigidity
bradykinesia
on/off fluctuations
similar to fetal tissue implant |
|
|
Term
| how does deep brain electrical stimulation work for treatment of PD? |
|
Definition
| small electrode is implanted into the brain and connected to a high frequency stimulator, which is reversible and controllable |
|
|
Term
| in deep brain electrical stimulation, where is the electrode implanted for treating tremors? |
|
Definition
| ventral intermediate thalamus |
|
|
Term
| in deep brain electrical stimulation, where is the electrode implanted for treating bradykinesia? |
|
Definition
|
|
Term
| what neurotrophic factor can be used with or without fetal tissue implant for treatment of PD? |
|
Definition
| GDNF - glial derived neurotrophic factor |
|
|
Term
| how would GDNF work in treatment of PD? |
|
Definition
stimulates neuronal growth in cells in culture and in experimental animals
under investigation for treatment of PD |
|
|
Term
| what is the goal of investigational gene therapy for treatment of PD? |
|
Definition
| goal is to insert the gene for tyrosine hydroxylase (TH) into the patients own fibroblasts (so there are no immunological problems) which are then returned to the patients brain |
|
|
Term
| levels of tyrosine hydroxylase in PD? |
|
Definition
| low due to loss of TH containing enzymes |
|
|
Term
| what is the rate limiting enzyme in DA synthesis? |
|
Definition
| tyrosine hydroxylase (TH) |
|
|
Term
You have recently diagnosed your patient, a 35 yo AA male with PD. Although this disorder is more common with increasing age, the age of onset is variable. You prescribe L-dopa for your patient b/c it is shown to be an effective treatment for PD. You must also inform your patient of the prognosis of his disorder, describing the symptoms to enable him to adjust to this disability. Which one of the following is most strongly a/w PD?
a. Bradykinesia
b. Petite grand mal
c. Choreic gait
d. Central pontine dysfunction
e. Supranucler palsy |
|
Definition
|
|
Term
A patient on medication develops severe HTN after eating some cheese. Which is the most likely combo of substances found in the cheese and medication to cause this reaction?
a. Ergotamine and amphetamine
b. Palmitate and reserpine
c. Tyramine and selegiline
d. Butyrate and propanolol
e. DA and phentolamine |
|
Definition
| c. Tyramine and selegiline |
|
|
Term
| how many americans have AD? |
|
Definition
|
|
Term
| what are potential contributing factors to AD (4)? |
|
Definition
1. mutations
2. oxidative damage
3. head trauma
4. high cholesterol, heart disease, high BP |
|
|
Term
| how is preliminary diagnosis for cognitive decline in AD made? |
|
Definition
| physical, psychological, and neuro exam + patient's medical history |
|
|
Term
| how is diagnosis for amyloid plaque in AD made? |
|
Definition
| PET scan using radiolabeled compounds which bind with high specificity to amyloid plaques |
|
|
Term
| how is a conclusive diagnosis of AD made? |
|
Definition
at autopsy
amyloid plaques in spaces between neurons containing insoluble peptides of amyloid beta protein |
|
|
Term
| AD is associated with diminished levels of what NT? |
|
Definition
|
|
Term
| what is the goal of drugs to treat AD? |
|
Definition
| increase brain levels of Ach by inhibiting AchE |
|
|
Term
what 4 drugs are used to treat AD?
what type of drug are they? |
|
Definition
inhibitors of AchE
1. tacrine
2. donepezil
3. rivastigmine
4. galantamine |
|
|
Term
| mechanism of action of inhibitors of AchE used to treat AD? |
|
Definition
selective inhibition of AchE in the CNS
very little effect on peripheral AchE |
|
|
Term
| effect of inhibitors of AchE used to treat AD? |
|
Definition
| produce modest improvement in cognition |
|
|
Term
| adverse side effects of AchE inhibitors (5)? |
|
Definition
1. nausea
2. diarrhea
3. vomiting
4. insomnia
5. hepatotoxicity |
|
|
Term
| what side effect is dose limiting for tacrine? |
|
Definition
|
|
Term
what drug was approved in 2008 for treatment of mild to moderate dementia?
why is it better? |
|
Definition
rivastigmine transdermal patch
has lower adverse side effects than the oral form |
|
|
Term
| what is a rapidly acting reversible inhibior of AchE? |
|
Definition
|
|
Term
| how has physostigmine been altered to be used for treating AD? |
|
Definition
now in a sustained release form
was of limited effect before because so fast acting |
|
|
Term
| what type of drug is memantine? |
|
Definition
| an open channel blocker of NMDA receptors used to treat AD |
|
|
Term
| memantine may protect neurons from what? |
|
Definition
| over-stimulation caused by excess glutamate |
|
|
Term
| what are 5 other AD therapies under development? |
|
Definition
1. disruption or inhibition of formation of amyloid
2. implants of patient's own skin cells genetically modified to produce nerve growth factor
3. ampalex facilitates the function of a subtype of glutamate receptors (AMPA) by increasing the amount of current flow that takes place when glutamate binds to the receptor
4. statins, which lower cholesterol, are being examined because the mechanism for clearing cholesterol from the body may be involved in the development of AD
5. nutritional supplements, including antioxidant vit E, folic acid, B6, and B12 - to decrease homocystein which has been reported to be high in AD |
|
|
Term
| what are 3 therapies under development to disrupt or inhibit formation of amyloid in AD? |
|
Definition
1. inhibit amyloid production with inhibitors of secretase needed for assembly of amyloid
2. NSAIDs in high doses have been shown in tissue culture and in mice to have a protective effect by decreasing the formation of amyloid beta peptides
3. alzhemed (a sulfated glycosaminoglycan mimetic) binds to amyloid beta peptides and blocks aggregation |
|
|
Term
During the post-mortem of a 65 yo male, neurofibrillary tangles and neuritic plaques with an amyloid core were found. Based on this, it could be determined that the patient was suffering from AD. AD has been a/w certain neurochemical changes in the brain, primarily:
a. Increased Ach
b. Increased DA
c. Decreased DA
d. Decreased Ach
e. Decreased acetyl CoA |
|
Definition
|
|
Term
67 yo woman who was once an accomplished pianist is brought to her physicians office by her husband. He states that over the course of the past 5 years she has lost the ability to play the piano, had difficulty recognizing her grandchildren, she has not been able to plan their daily activities, she has forgotten things left cooking on the stove, and at night she has been wandering through the house with an absent look on her face. She is beginning to demonstrate difficulty in recalling the names of common objects, and her speech is limited to simple 2 or 3 word sentences. Prescribe?
a. Rivastigmine
b. Fluoxetine
c. Amantadine
d. Bromocriptine
e. Phenelzine |
|
Definition
|
|
Term
| treatment of inherited dystonia? |
|
Definition
| DOPA/carbidopa produces good response without adverse side effects |
|
|
Term
| treatment of progressive supranuclear palsy? |
|
Definition
|
|
Term
| what is important about treating progressive supranuclear palsy? |
|
Definition
DOPA/carbidopa treatment of this condition has NO beneficial effect and only adverse reactions are seen
if its misdiagnosed and treated as PD - can be harmful |
|
|
Term
| etiology of huntington's disease? |
|
Definition
| inherited, autosomal dominant disorder |
|
|
Term
| characteristics of huntington's disease? |
|
Definition
progressive brain degeneration
progressive dementia and severe choreiform movements |
|
|
Term
| what drugs are used for reducing involuntary movements in huntington's disease? |
|
Definition
|
|
Term
| what drugs can be used for depression, paranoia, anxiety and psychoses seen with huntington's disease? |
|
Definition
fluoxetine
carbamazepine
clozapine |
|
|
Term
| what drug was recently approved by the FDA for treatment of chorea associated with huntington's disease? |
|
Definition
| tetrabenazine (a benzodiazepine) |
|
|
Term
|
Definition
| recently approved by the FDA for treatment of chorea associated with huntington's disease |
|
|
Term
| what is amyotrophic lateral sclerosis (ALS)? |
|
Definition
| degenerative neurological disease that primarily involves motor neurons |
|
|
Term
| ALS is characterized by what (7)? |
|
Definition
1. muscular atrophy
2. progressive weakness
3. fasciculations
4. spasticity
5. disarthria
6. dysphagia
7. resp compromise |
|
|
Term
| what drug is used in the treatment of ALS for spasticity? |
|
Definition
baclofen
a GABA-B agonist |
|
|
Term
| mechanism of action of riluzole? |
|
Definition
| blocks glutamate dependent neurotransmission in the CNS |
|
|
Term
| effect of riluzole in treating ALS? |
|
Definition
| modest decrease in disease progression and increase (2-3 months) in survival and ventilator-free time in some patients |
|
|
Term
| what 3 drug/types are used to treat ALS? |
|
Definition
1. GABA-B agonist - baclofen - for spasticity
2. antidepressant agents
3. riluzole - may decrease progression and increase survival modestly in some patients |
|
|
Term
| what other treatment may be useful in treated ALS? |
|
Definition
|
|
