PBL 1 Flashcards
1
Q
define mad-par
A
benserazide (Dopa decarboxylase inhibitor) and levodopa is contained inside it, it forms the drugs that make up antiparkinsons agents
2
Q
define rotigotine
A
– this is a dopamine agonist used in Parkinson’s disease, can be used in a transdermal patch which is useful in the later stages of the disease
3
Q
define selegilline
A
this is an MAO inhibition that works by slowing the breakdown of substances such as dopamine, noradrenaline and serotonin
4
Q
define micrographic
A
this is the progression to progressively smaller handwriting, it is associated with neurodegenerative disorders of the basal ganglia
5
Q
define vitamin E
A
vitamin that dissolves it fat, it is found in many foods including vegetable oils, cereals, meat, poultry, eggs, fruits, and vegetables – it can cause nerve problems
6
Q
define cogwheel Rigidity
A
– this is muscular rigidity in which passive movements of the limbs causes a ratchet like start and stop movements through the range of motion of a joint
7
Q
describe what the cause of Parkinson’s is due to
A
- Due to loss of dopaminergic neurones in the substanita nigra pars compacta which usually project and innervate the caudate and putamen
- 80% of dopamine neurones have to degenerate before the clinical symptoms manifest themselves
- Causes a shift towards the indirect pathway
- Shows both motor and non motor conditions
- Associated with the SNCA gene which codes for protein alpha synuclein – this increase the risk of developing Parkinson’s significantly
8
Q
describe the motor and non motor characteristics of Parkinson’s
A
Characteristics
- Resting tremor
- Slowness of movement (bradykinesia)
- Muscular rigidity
- Minimal facial movements
Non motor characterstics (usually precede motor functions by 12-15 years)
- Olfactory dysfunction
- Sleep disturbance
- Depression
- Autonomic dysfunction
- Dementia (late phase)
9
Q
describe the histology of Parkinson’s
A
- Loss of dopaminergic cells in substantia nigra pars compacta
- And presence in neurones of Lewy bodies ( these are intracellular formation that are enriched in the protein alpha-synuclein)
- These Lewy bodies are also presence in other conditions such as dementia
- There are also losses of cells throughout the nervous system
10
Q
describe the drug Madopar
A
- This is L dopa with a peripheral decarboxylase inhibitor (Benserazide) this prevents the conversion of L dopa to dopamine in the periphery which can cause nausea and vomiting, this means that L dopa is only converted to dopamine once past the blood brain barrier
- L-dopa is converted to dopamine via dopa decarboxylase and this increases the concentration of dopamine present
- Beneserazide inhibits the conversion of L dopa to dopamine in the periphery
11
Q
describe L dopa and its side effects
A
- After a few years use the efficacy of L dopa tends to wear off
- The effects of the Parkinson’s comes back worse than before even with increased dose
- This is an on off effect of L dopa where there is dramatic fluctuations in performance due to the intake of L dopa
- In patients with this effect L dopa is combined with benserazide or carbidopa both peripherally acting dopa decarboxylases
- Side effects include: nausea and vomiting, postural hypotension, psychosis, impuslve control disorders, excessive day-time sleepiness
12
Q
describe dopamine agonists
A
- These include ropinirole, pramipexole, rotigotine, pergolide, bromocriptine, cabergoline
- Rotigotine - dopamine agonist which can be used as transdermal patch – important as the disease progresses and they can no longer swallow
- Dopamine agonist usually less efficious than L dopa but they have fewer side effect
- Prescribed before
13
Q
describe MOA inhibitors
A
MAOB inhibitors (protect residual dopamine against oxidation)
- rasagiline, selegiline - this prevents the breakdown and oxidation of dopamine
14
Q
describe the prescribing hierarchy
A
- L dopa - increases motor system control most 0 increase risk of motor complications and other adverse events
- dopamine agonists - increases motor system control the 2nd most - decrease risk of motor complications but has other adverse effects
- MAOb inhibitors - increases motor system control the least - decrease risk of motor complications but has other adverse effects
- mild motor disability and no cognitive impairment - begin MAOb inhibitor
- mild/moderate motor disability and no cognitive impairment - begin dopamine agonist
- moderate/severe disability and age 70-75+ years or with significant comorbidity including cognitive impairment - begin L Dopa and plus or minus COMT inhibitor
15
Q
describe the new treatments available for parkinsns
A
- Vitamin E – vitamin E is an antioxidant and there is increased idea that there is a lot of oxidation in parkinsons and this can reduce this
- long term survivial of human embryonic mesencephalic graft in parkisnons disease, - the graft is functional and releases dopamine (after administration of metamphetamine) the dopamine released by the graft can displace the radioalabelled raclopride
16
Q
describe the link between parkinsons, depression and memory
A
- depression and dementia are co-morbidities of parkisnons
- might be that drugs that treat depression can cause parkinsons disease
- can be decreased levels of serotonin present in the brain
17
Q
describe the nuclei of the basal ganglia
A
- Input nuclei – caudate nucleus and putamen
- Intrinsic nuclei – external globus pallidus, subthalamic nucleus, pars compact of the substantia nigra
- Output nuclei – internal globus pallidus, pars reticulata of the substantia nigra
18
Q
what do the globes pallidus and putamen form
A
- Globus pallidus and putamen for the lentiform nucleus
19
Q
What does the caudate and putamen form
A
corticostriatium
20
Q
describe the substantial nigra
A
- Divides in pars compacta and pars reticulata
- Pars compacta – cells produce dopamine, these are the cells that are broken down in Parkinson’s disease and are degenerated
- Pars reticulata – receives input from the striatium but sends it outside the basal ganglia to control head and eye movement
21
Q
describe where the sub thalamic nuclei are
A
- Inferior to the thalamus and right above the substanita nigra
22
Q
describe the globes palladium
A
- Made out of the internal and external segment
- Intenral segmenet sends output to the thalamus
- External segement relays information between other basal ganglia nuclei and the globus pallidus internal segement
23
Q
describe the blood supply to the basal ganglia
A
Caudate
- Middle cerebral artery (body)
- Anterior cerebral artery (anterior)
Putamen
- Middle cerebral artery
- Anterior cerebral artery (anterior)
Globus pallidus
- Middle ceberal artery
- Anterior choroidal
Internal capsule
- Middle cerebral artery (middle)
- anterior cerebral artery (anterior limb)
- anterior choroidal (posterior limb)
24
Q
What is the function of the basal ganglia
A
- Initiation of movement
- Together with the cerebellum the basal ganglia modify movement on a minute to minute basis
- Process information relaying to emotion, motivation and cognition
25
describe the direct pathway
- D1 via the substantial migration pars compacta activates the striatum via dopamine
- striatum consist of the caudate and putamen
- the striatum sends an inhibitory signal to the globes pallidus internal segment and the substantial nigra pars reticulate via GABA
- these both send negative signals to the thalamus nuclei
- there is disinhibition of the thalamus (VA/VL nuclei) which leads to increased excitatory of the frontal motor cortex via glutamate
26
describe the indirect pathway
neurones in the subtanita migration pars compacta are expressed D2
- D2 gives an inhibitory signal tot he striatum (putamen and caudate`0
- this gives an inhibitory signal via GABA to the globes pallidus external
- GABA again gives an inhibitor signal to the sub thalamic nucleus
- this gives a excitatory signal to the globes pallidus internal via glutamate
- which gives an inhibitory signal tot he thalamus via GABA
- this leads to a less excitatory signal in the motor cortex and inhibits the motor cortex instead of disinhibition as seen in the direct pathway
27
when do patients experience complications with L dopa
within 5 years = mainly due to disease progression
28
name the 3 effects to do with L dopa
- on off effect = motor fluctuations
- dyskinesia
- neuropsychiatric problems
29
describe the on off effect experienced in L dopa
In this scenario Louis experiences: normal mobility (on) and then freezing (off).
End-of-dose deterioration: wearing-off clinical benefit that increases after years of usage.
o Often due to change in sensitivity of dopamine receptors.
30
in patients with motor fluctuations what is L dopa better combined with
L-DOPA/benserazide
L-DOPA/carbidopa.
these are peripheral dopa decabroyxlase inhibitors
31
what are two types of dyskinesia
- chorea like movement
| - dystonias
32
describe the two type of dyskinsia movement
Chorea-like movements: hyperkinetic, purposeless dance-like movements.
Dystonias: intense and sustained muscle contractions.
Peak-dose dyskinesia and wearing-off dystonias are due to fluctuations in the level of dopamine
produced intracerebrally after each dose of L- Dopa.
33
what are the future drug treatments used to treat speicifcly L dopa induced dyskinesia
Alpha2-receptor antagonists.
Glutamate receptor antagonists.
5-HT1A receptor agonists.
34
what do COMT inhibitors do to L dopa
use of L-DOPA combined with entacapone (inhibitor of enzyme catechol-O-methyl-
transferase/COMT) may alleviate dystonias and motor fluctuations in long-term management.
COMT inhibitors prolong the effect of L-DOPA.
35
when are dopamine agonists prescribed
Less efficacious than L-DOPA
| Often prescribed before prescription of L-DOPA.
36
what are non motor complications of L dopa
Tingling, pain, akathisa, autonomic dysfunction.
37
what are neuro-psychiatric complications of L dopa
Hallucinations, mood changes, hypersexuality, nightmares.
38
name two common co morbidities to do with parkinsons
Depression: common to develop in patients with
Parkinson’s Disease.
Dementia: often a co-morbidity with Parkinson’s’.
39
name the anticholinergic side effects
- dry mouth
- constipation
- confusion
- blurred vision
40
what is the intimal treatment for Parkinson
- start with dopamine agonists to delay the introduction of L dopa which will lead to motor complications
41
what treatment is used for mild symptoms
Selegiline or a newer drug Rasagiline (MAOb Inhibitor). OR
Anticholinergic drug= used for tremor (e.g. Orphenadrine,
Procyclidine, Trihexyphenidyl.
o Dry mouth, constipation, confusion, blurred vision
(important to know side effects!)
Drugs that released dopamine.
These drugs are less efficacious than L-DOPA, and are used as ADJUNCTIVE THERAPHY.
42
what treatment is used for severe treatments
Severe Symptoms
Use of L-DOPA, however leads to symptoms described above.
Studies have shown that addition of selegiline/rasagiline to L-DOPA improves motor fluctuations and
allows for a reduction of L-DOPA dose by 20-30%.
o Benefit is short lived and only works in ½ patients.
Can also be combined with entracapone/tolcapone (COMT inhibitors).
o Enhances effects of L-DOPA
43
what surgical procedures can be used
Pallidotomy/deep brain stimulation of the subthalamic nucleus can alleviate symptoms.
o Not available on a large scale.
o Patients must adhere to certain criteria.
Depression and dementia make it unsuited.
- or you can use a human embryonic mesencephalic graft
44
1. Name the neurotransmitters released by the corticostriatal and striatopallidal pathways. (1 mark)
corticostriatal = glutinate
striatopallidal = GABA
45
2. Describe the effects of D1 receptor activation on striatal efferent circuitry. (2 marks)
```
D1 receptor activation causes the activation of the direct pathway (½ mark) by which the internal GP is
inhibited (½ mark). This causes the disinhibition of the thalamus (½ mark) and consequently the activation of
the cortex (½ mark).
```
46
3. What is alpha-synuclein, where is it found in the brain and what is its genetic link with Parkinson’s
disease? (2 marks)
Alpha-synuclein is a protein found in Lewy bodies in neurons (½ mark); Lewy bodies are a major
histopathological feature of Parkinson’s disease (½ mark).
The gene for alpha-synuclein is the SNCA gene; mutations associated with this gene (e.g. PARK1/4) have been
identified as a genetic risk factor for Parkinson’s disease (1 mark).
47
4. List and briefly describe three long-term complications of L-DOPA therapy. (3 marks)
Motor fluctuations: include “on-off” phenomenon in which sudden and dramatic fluctuations of motor
performance occur; periods of normal mobility (on) followed by sudden ‘freezing’ (off). End of dose
deterioration and delayed (or ‘no on’- freezing) responses also occur (1 mark).
Dyskinesia’s: include choriform movements (purposeless involuntary dance-like movements) and dystonias
(sustained intense muscle contractions) (1 mark).
Neuro-psychiatric problems: hallucinations, delirium, mood changes, sleep disturbance and nightmares (1
mark).
48
5. What is rotigotine and what is its route of administration? (2 marks)
Dopamine receptor agonist (non-selective agonist); high affinity for the dopamine D1, D2, D3 receptors, and to
a lesser extent D4 and D5 receptors (1 mark)
It is applied transdermally as a patch. (1 mark)
