Treatment of Parkinsons Disease Flashcards
What kind of disorder is idiopathic Parkinsons diesae (IPD)?
Neurodegenerative disorder
What kind of clinical course does IPD take?
Progressive clinical course, with no cure but very slow progession, can take 20-30+ years
What are the motor clinical features of Parkinsonism?
- Tremor
- Rigidity
- Bradykinesia
- Postural instability
Describe the Parkinsonism tremor
- Very characteristic
- Low frequency, 3-5Hz
- ‘Pill rolling’
- Resting tremor, abolished by movement
What kind of rigidity might arise in Parkinsonism?
- Lead pipe rigidity
- Cog-wheel rigidity
What is lead-pipe rigidity?
Resistance in the whole range of movements
How is cogwheel rigidity demonstrated?
By slow movement of the wrist
How does bradykinesia manifest in Parkinsons?
- Slow movement
- Reduced facial expressions and blinking
- Small writing
What causes bradykinesia in Parkinsons?
Low dopamine, and disturbance of other neurotransmitter levels
How does postural instability manifest in Parkinsons?
- Forward flexed shuffling gait
- Difficulty initiating and terminating
What causes postural instability in Parkinsons?
Low dopamine
Why is there low dopamine in Parkinsons?
Dopamine producing neurones in the substantia niagra are lost
What % of dopamine producing neurones in the substantia niagra have to be lost to produce clinical signs?
50%
What are the non-motor manifestations of Parkinson’s Disease?
- Mood changes
- Pain
- Cognitive change
- Urinary symptoms
- Sleep disorders
- Sweating
What sleep disorders might occur in Parkinsons?
Patient doesn’t become atonic, and may act out violent dreams
What % of PD patients have dyskinesia at 15 year follow up?
94%
What kind of dyskinesia do patients with PD have?
Involuntary writhing movements
What might cause the dyskinesia in PD?
Treatment side effects
What is meant by somnolenece?
Sleep attacks
What is the problem with sleep attacks in Parkinsons?
They affect ability to drive
What speech problems does Parkinsons cause?
Hypophonia - eventually can hardly speak at all
How is a diagnosis of IPD made?
- Clinical features
- Exclusion of other causes of Parkinsonism
- Response to treatment
- Structural neurological imaging
- Functional neurological imaging
What are the causes of Parkinsonism, other than IPD?
- Drug induced Parkinsonism
- Vascular Parkinsonism
- Progressive supranuclear palsy
- Multiple Systems Atrophy
- Corticobasal Degeneration
What can cause drug-induced Parkinsons?
Anti-psychotics, e.g. sodium valproate
What are the features of vascular Parkinsonism?
Bradykinesa, not so much a tremor
What are the characteristics of progressive supranuclear palsy and multiple systems atrophy?
Axial ridigity in the trunk, not so much in the arms
How is multiple systems atrophy treated?
Glucocortisone
What kind of Parkinsonism produces normal neurological imaging?
- Idiopathic
- Drug induced
What functional neurological imaging is used in the diagnosis of IPD?
- SPECT
- PET
What are the pathological features of Parkinsons Disease?
- Neurodegeneration
- Lewy bodies
- Loss of pigment
- Reduced dopamine
What is meant by loss of pigment in Parkinson’s disease?
Degeneration of pigmented cells in substantia niagra
At what % loss of pigment do symptoms arise in Parkinson’s disease?
50%
Why do symptoms not occur until there is a 50% loss of pigment in Parkinsons disease?
Because other neurones can compensate by working harder, by increasing turnover and upregulating receptors
Draw a diagram illustrating the basal ganglia circuit?
What does loss of dopaminergic neurones in the substantia niagra in Parkinsons disease result in?
Reduced inhibition in neostriatum, which allows increased production of ACh. This chain of abnormal signalling leads to impaired mobility
Describe the steps in catecholamine synthesis?
L-Tyrosine → L-DOPA → Dopamine → Noradrenaline → Adrenaline
What catalyses the conversion of L-Tyrosine to L-DOPA?
Tyrosine hydroxylase
What catalyses the conversion of L-DOPA to dopamine?
DOPA decarboxylase
What catalyses the conversion of dopamine to noradrenaline?
Dopamine B-hydroxylase
What catalyses the conversion of noradrenaline to adrenaline?
Phenylethanolamine n-methyltransferase
What is dopamine degraded into?
- 3,4-dihydrophenyl-acetic acid, then to homovanillic acid
- 3-methoxytyramine, then to homovanillic acid
What catalyses the conversion of dopamine to 3,4-dihydrophenyl-acetic acid?
- Monoamine oxidase
- Aldehyde dehydrogenase
What catalyses the conversion of 3,4-dihydrophenyl-acetic acid to homovanillic acid?
Catechol-O-methyl transferase COMT
What catalyses the conversion of dopamine to 3-methoxytyramine?
Catechol-O-methyl transferase COMT
What catalyses the conversion of 3-methoxytyramine to homovanillic acid?
- Monoamine oxidase
- Aldehyde dehydrogenase
Give the steps in neurotransmission
- Synthesis of neurotransmitter and formation of vesicles
- Transport of neurotransmitter down the axon
- Action potential travels down axon
- Action potential causes calcium to enter, evoking release of neurotransmitter
- Neurotransmitter attaches to receptor, exciting or inhibiting the postsynaptic neurone
- Separation of the neurotransmitter molecules from receptors
- Reuptake of neurotransmitter to be recycled
- Vesicles wihout neurotransmitter trasported back to the cell body
What is a DAT brain scan?
A test to look at the level of dopamine receptor cells in the brain using a small amount of iodine based radioactive material.
The findings are abnormal in Parkinsons disease
Is a DAT scan diagnostic of Parkinsons?
No
What are the drug classes used in the treatment of the movement disorder in Parkinsons disease?
- Levodopa (L-DOPA)
- Dopamine receptor agonists
- MAOI type B inhibitors
- COMT inhibitors
- Anticholinergics
- Amantidine
Why is L-DOPA used to treat Parkinsons, rather than dopamine?
Because L-DOPA can cross the blood brain barrier by active transport, but dopamine cannot
What happens to levodopa once it crosses the blood brain barrier?
It must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine
What is the problem with levodopa in the treatment of Parkinsons diease?
If there are fewer remaining dopaminergic cells, there is a less reliable effect of levodopa, and therefore you get motor fluctuations
How is levodopa administered?
Orally
How is levodopa absorbed?
By active transport
What is the absorption of levodopa in competition with?
Amino acids
What % of levodopa is inactivated in the intestinal wall?
90%
What inactivates levodopa in the intestinal wall?
- Monoamine oxidase
- DOPA decarboxylase
What is the half life of levodopa?
2 hours
What is the result of the short half life of levodopa?
- Short dose interval
- Fluctuations in blood levels, therefore symptoms
What % of levodopa is converted to dopamine in peripheral tissues?
9%
What % of levodopa is converted to dopamine in peripheral tissues?
DOPA decarboxylase
What % of levodopa enters the CNS?
<1%
What limits levodopas entry into the CNS?
Competes with amino acids for active transport across the blood brain barrier
What is L-DOPA sometimes used in combination with?
A peripheral DOPA decarboxylase inhibitor
What is co-careldopa?
L-DOPA with sinemet
What is co-beneldopa?
L-DOPA with madopar
What is the advantage of giving L-DOPA in combination with a peripheral DOPA decarboxylase inhibitor?
- Reduced dose required
- Reduced side effects
- Increased L-DOPA reaching brain
Why does a peripheral DOPA decarboxylase inhibitor increase the amount of L-DOPA reaching the brain?
It prevents L-DOPA metabolism in the gut and peripheries
What are the advantages of L-DOPA?
- Highly efficacious
- Low side effects
What are the side effects of L-DOPA?
- Nausea/anorexia
- Hypotension
- Psychosis
- Tachycardia
Why does L-DOPA cause nausea/anorexia?
Due to its effect on vomiting centres
Does L-DOPA cause central or peripheral hypertension?
Both
What are the disadvantages of L-DOPA?
- Precursor, so needs enzyme conversion
- Long term problems
What are the long term effects of L-DOPA?
- Loss of efficacy
- Involuntary movements
- Motor complications, including dyskinesia, dystonia, and freezing
Why is there a loss of efficacy with long term L-DOPA use?
Because it is only effective in the presence of dopaminergic neurones, which reduce as Parkinsons progresses
What does L-DOPA interact with?
- Pyridoxine
- MAOIs
What effect does pyridoxine have on L-DOPA?
It increases peripheral resistance of L-DOPA
What happens when MAOIs are given with L-DOPA?
RIsk hypertensive crisis
What are the categories of dopamine receptor agonists?
- Ergot derived
- Non-ergot
- Patch
- Subcutaneous
Give three examples of ergot derived dopamine receptor agonists
- Bromocryptine
- Pergolide
- Cabergoline
Give two examples of non ergot dopamine receptor agonists
- Ropinirole
- Pramipexole
Give an example of a patch dopamine receptor agonist
Rotigotine
Give an example of a subcutaneous dopamine receptor agonist
Apomorphine
How can dopamine receptor therapy be given?
- De novo therapy
- Add on therapy
What patients are given apomorphine?
Only those with severe motor fluctations
What are the advantages of dopamine receptor agonists?
- Direct acting
- Less dyskinesias/motor complications
- Possible neuroprotection
What are the disadvantages of dopamine receptor agonists?
- Less efficacy than L-DOPA
- Causes impulse control disorders
- More psychiatric side effects, which are dose limiting
- Expensive
What are the features of impulse control disorders?
- Pathological gambling
- Hypersexuality
- Compulsive shopping
- Desire to increase dosage
- Punding
What are the side effects of dopamine receptor agonists?
- Sedation
- Hallucinations
- Confusion
- Nausea
- Hypotension
What is the function of monoamine oxidase B?
It metabolises dopamine
Where does monoamine oxidase B action predominate?
In dopamine containing regions in the brain
What effect do monoamine oxidase B have on dopamine?
They enhance it
Give two examples of monoamine oxidase B inhibitors
- Selegiline
- Rasagaline
Can monoamine oxidase B inhibitors be used alone?
Yes
What effect do monoamine oxidase B inhibitors have on L-DOPA?
They prolong the action
What effect do monoamine oxidase B inhibitors have on Parkinsons symptoms?
- Smooths out motor response
- May be neuroprotective
Give two examples of catechol-O-methyl transferase (COMT) inhibitors
- Entacapone
- Tolcapone
Do COMT inhibitors cross the blood brain barrier?
- Entacapone doesn’t
- Tolcapone does, but its main effect is peripheral
What effect do COPT inhibitors have?
They reduce peripheral breakdown of L-DOPA to 3-O-methyldopa, which competes with 3-O-methyldopa active transport into the CNS
Can COMT inhibitors be used alone?
No
What are COMT inhibitors used in combination with?
L-DOPA and a peripheral DOPA decarboxylase inhibitor, e.g. Stalevo
What effect do COMT inhibitors have on L-DOPA?
It prolonges the motor response to L-DOPA, and reduces symptoms of ‘wearing off’
What is the principle behind the use of anticholinergics in Parkinsons?
Acetylcholine may have antagonistic effects to dopamine
Give three examples of anticholinergics
- Trihexyphenidydyl
- Orphenadrine
- Procyclidine
What are the advantages of anticholinergics?
- Treats the tremor
- Doesn’t act via dopamine systems
What are the disadvantages of anticholinergics?
- No effect of bradykinesia
- Side effects, including confusion and drowsiness
What is the mechanism of action of amantadine?
Uncertain, but possible enhanced dopamine release or anticholinergic NMDA inhibition
What are the advantages of amantadine?
Few side effects
What are the disadvantages of amantadine?
- Poorly effective
- Little effect on tremor
When is surgery of value in Parkinsons disease?
In highly selected cases;
- Dopamine responsive
- Significant side effects with L-DOPA
- No psychiatric illness
What is done in surgery for Parkinsons?
- A lesion is made, in the thalamus for a tremor, or in the globus pallidus interna for dyskinesias
- Deep brain stimulation to the subthalamic nucleus
