PBL 1 Flashcards
define mad-par
benserazide (Dopa decarboxylase inhibitor) and levodopa is contained inside it, it forms the drugs that make up antiparkinsons agents
define rotigotine
– 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
define selegilline
this is an MAO inhibition that works by slowing the breakdown of substances such as dopamine, noradrenaline and serotonin
define micrographic
this is the progression to progressively smaller handwriting, it is associated with neurodegenerative disorders of the basal ganglia
define vitamin E
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
define cogwheel Rigidity
– 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
describe what the cause of Parkinson’s is due to
- 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
describe the motor and non motor characteristics of Parkinson’s
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)
describe the histology of Parkinson’s
- 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
describe the drug Madopar
- 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
describe L dopa and its side effects
- 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
describe dopamine agonists
- 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
describe MOA inhibitors
MAOB inhibitors (protect residual dopamine against oxidation)
- rasagiline, selegiline - this prevents the breakdown and oxidation of dopamine
describe the prescribing hierarchy
- 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
describe the new treatments available for parkinsns
- 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
describe the link between parkinsons, depression and memory
- 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
describe the nuclei of the basal ganglia
- 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
what do the globes pallidus and putamen form
- Globus pallidus and putamen for the lentiform nucleus
What does the caudate and putamen form
corticostriatium
describe the substantial nigra
- 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
describe where the sub thalamic nuclei are
- Inferior to the thalamus and right above the substanita nigra
describe the globes palladium
- 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
describe the blood supply to the basal ganglia
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)
What is the function of the basal ganglia
- 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
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
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
when do patients experience complications with L dopa
within 5 years = mainly due to disease progression
name the 3 effects to do with L dopa
- on off effect = motor fluctuations
- dyskinesia
- neuropsychiatric problems
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.
in patients with motor fluctuations what is L dopa better combined with
L-DOPA/benserazide
L-DOPA/carbidopa.
these are peripheral dopa decabroyxlase inhibitors
what are two types of dyskinesia
- chorea like movement
- dystonias
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.
what are the future drug treatments used to treat speicifcly L dopa induced dyskinesia
Alpha2-receptor antagonists.
Glutamate receptor antagonists.
5-HT1A receptor agonists.
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.
when are dopamine agonists prescribed
Less efficacious than L-DOPA
Often prescribed before prescription of L-DOPA.
what are non motor complications of L dopa
Tingling, pain, akathisa, autonomic dysfunction.
what are neuro-psychiatric complications of L dopa
Hallucinations, mood changes, hypersexuality, nightmares.
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’.
name the anticholinergic side effects
- dry mouth
- constipation
- confusion
- blurred vision
what is the intimal treatment for Parkinson
- start with dopamine agonists to delay the introduction of L dopa which will lead to motor complications
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.
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
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
- Name the neurotransmitters released by the corticostriatal and striatopallidal pathways. (1 mark)
corticostriatal = glutinate
striatopallidal = GABA
- 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).
- 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).
- 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).
- 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)
