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Flashcards in Neurodegenerative disorders Deck (32):

what are the characteristics of a neurodegenerative disorder ?

loss of neurones from CNS and some motor neurones


what is a major problem with treating neurodegenerative disorders?

as the disease progresses the symptoms get worse
only have treatments for symptoms


what are examples of neurodegenerative diseases ?

PD - onset can be any age but generally over 70
HD- onset is about middle life
AD- >60yrs, at >85yrs 20-25% people have it
FTD/picks- onset in old age
motor neurones- middle life


define dementia:

an acquired persistent intellectual impairment involving at least 3 of the following
- memory
- language
- visuospatial skills
- emotion/personality
- cognitive/executive functions


general info on pd :

first described by james palsy in 1817 - shaking palsy
common worldwide
incidence increase >70yrs older you are the more likely you are to develop it
akinetic rigid syndrome= loss of movement and increased muscle tone


what is the pathology of PD?

-loss of neurones in the substantia nigra
-dopaminergic neurones affected
-loss of nigro-striatal pathways direct/indirect
-direct pathway facilitates movement
-indirect pathway inhibits movement


what does treatment often try to recover in PD?

tries to recover the loss of dopamine neurons in the stn
- increase the amount of DA in remaining neurons
- prevent breakdown of DA
- increase release of remaining DA
- use DA agonists
- alter acetylcholine activity in striatu


what approaches are taken to increase DA activity ?

replace DA with L-DOPA
decrease DA breakdown with MAO inhibitors and COMT inhibitors
increase DA release with amantidine
DA agonists such as bromocriptine and pergolide


what approaches are taken to decrease ACh activity ?

antimuscarinics such as benzhexol and orphenadrine


why is L-DOPA given ?

tyrosine is the aa that forms DA but it cannot cross BBB
L-DOPA is the precursor of DA and it can cross BBB and be taken up by DA neurones
- taken up into neurons by carrier mechanism
- this increases the amount of DA in DA neurones so it releases mre DA upon AP
- it can also be taken up by glial cells


why is L-DOPA not taken orally ?

although it can be taken orally, 90% of it is lost by the liver and even once it is absorbed by the intestine it can be broken down readily in the periphery causing the loss of another 9% so therefore only 1% reaches the brain


what happens to 90% of L-DOPA?

it is metabolised in the intestinal wall by DOPA decarboxylase or MAO


what is usually given alongside L-DOPA and why ?

- because it inhibits DOPA decarboxylase and it cannot cross the BBB so it enables the L-DOPA to reach the brain in sufficient amounts


what are the adverse effects of L-DOPA ?

'on-off' effect - this is a serious side effect in which there is a worsening of PD symptoms aas DA concentration drops - the mechanism is unknown
nausea, vomitting, anorexia- activates the chemoreceptive trigger zone
dyskinesias- too much L-DOPA causing then too much movement
tachycardia, extrasystoles
hypotension - could be due to central sympathetic inhibition
insomnia,, confusion, schizophrenic effects- these are due to increase DA turnover


what do PD patients become very adept in ?

in knowing how much L-DOPA they need to take and when


what are often used to control the side effects caused by increased DA turnover ?

neuroleptics- with no D2 action


what happens with the side effects of LDOPA ?

they are greater with time because the dose of L-DOPA needs to be increase and so therefore with time it is no longer effective


what do MAO inhibitors do ?

they inhibit MAO and therefore reduce the breakdown of DA
useful first line therapy
e.g. selegiline


what is selegiline ?

= deprenyl
MAO b inhibitor so has fewer side effects
may have neuroprotective effects - thought it may have antioxidative effects to slow nerve damage
few side effects
potentiates central side effects of L-DOPA
effective on its own in the early stages but ineffective in later stages


what do COMT inhibitors do ?

block COMT to increase the concentration of DA and L-DOPA
e.g entacapone - first licensed in 1998


when are COMT inhibitors often used ?

for patients with 'on-off' problems
usually used in combo with L-DOPA
it smooths out variations with DA levels


what are the adverse effects of COMT inhibitors ?

aggravate L-DOPA dyskinesias
nausea- action at chemoreceptive trigger zone
abdo pain
dry mouth


what does amantadine do ?

increases DA release - it is an amphetamine
useful in the early stages
generally well tolerated
can cause confusion and hallucinations in the elderly


what are bromocriptine and pergolide?

dopamine agonists
bromocriptine is a d1 and d2
pergolide is d2 selective
given alone or with L-DOPA
half life of 6-8 hours - need to take 2-3 times a day


what are the adverse effects of bromocriptine and pergolide ?

nausea, vomitting- chemoreceptive trigger zone
severe hypotensive effects
sometimes hallucinations


what are antimuscarinics?

block muscarinic receptors
e.g benzhexol and orphenadrine
most effective on tremor and drooling


what are the adverse effects of antimuscariniccs?

central effects- confusion, deluisions, hallucinations, drowsiness and mood changes


what happens once youve been diagnosed with PD?

you see a neurologist to control and tailor the treatment to the patient
- effects of different drugs vary between individuals
- treatment has to be changed overtime


what are the 3 main surgical procedures that can be used to treat PD?

implantable stimulators


what are lesion surgeries ?

motor thalamus- thalamotomy
globus pallidus- pallidotomy
subthalamus- subthalamotomy
these are severe procedures and not that effective and as the disease progresses the symptoms return


what are implantable stimulators ?

deep brain stimulators- done in absence of general anaesthesias
- electrode is advanced into the subthalamic nucleus and then look for lessening of symptoms
- effective for several years


what are grafts ?

adrenal medulla- mixed results and not its been dropped as a treatment idea- take chromaffin cells into the striatum because only they produce catecholamines
foetal nigral tissue- fetus' that have been aborted - shown limited success
GM fibroblasts- take skin cells from animals and modify them to produce DA and put them back into animals to see if DA produced- problem was that the cells kept dividing
stem cells- need to develop a way to differentiate them into DA neurons and also stop them continually dividing
xenografts - take DA tissue from another animal however this has ethical issues