Neurodegenerative disorders Flashcards
(32 cards)
what is a major problem with treating neurodegenerative disorders?
as the disease progresses the symptoms get worse
only have treatments for symptoms
what are the characteristics of a neurodegenerative disorder ?
loss of neurones from CNS and some motor neurones
progressive
irreversible
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
PSN
CBGD
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 ?
carbidopa
- 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 diarrhoea 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
