4.2 Movement disorders Flashcards
What is Idiopathic Parkinsons disease (IPD)?
A progressive neurodegenerative disorder which affects motor function. (95% of cases of PD)
PD (incl IPD) is due to low dopamine and disturbance to other neurotransmitter levels
Motor symptoms of IPD improve with what medication?
Levodopa
Parkinsonism is an umbrella term for symptoms of Parkinson’s
List the 4 key symptoms (TRAP)
Tremor, Rigidity, Akinesia (bradykinesia), Postural instability
Give 4 non motor manifestations PD
- mood changes, anxiety, depression
- pain
- cognitive change
- hyposmia (reduced sense of smell)
- urinary symptoms
- sleep disorder
- sweating
Give the Prognosis/ progression of PD across 15 years
How is Parkinsons diagnosed?
Clinical – history and examination (differential diagnosis)
Exclude other forms of PD
Early referral to neurologist
Rarely SPECT
MRI for DD between Parkinsonian syndromes
Response to Treatment
What is SPECT and how is it used in the diagnosis of PD
Single photon emission computed tomography
Uses a labelled tracer - Ioflupane (123I), a dopamine analogue and view its presynaptic uptake in the brain. This would be abnormal in PD
- Left: normal brain showing strong dopamine uptake
- Right: PD fewer dopinergic neurons
What is the pathology of IPD?
A degenerative disorder of dopaminergic neurotransmission in the basal ganglia.
Results in dopamine depletion causing altered patterns of inhibition in the basal ganglia:
- strengthens indirect pathway
- increases inhibitory output
+ Other neurotransmitters involved
What would be seen in a brain scan of a patient with IPD
Loss of pigmentation in the substantia nigra and cell death in other deep cortical and brainstem nuclei + lewy bodies
How/why do Lewy bodies form?
α-synuclein protein misfolds and accumulates in the dopaminergic neurons ➞ synucleinopathy ➞ leads to cell death
Explain the direct vs indirect pathway
Direct = excitatory ➞ release neurons from inhibition
Indirect = inhibitory ➞ supress neurons further ‘a brake on the system’
What % of dopaminergic neuron loss is required before motor symptoms arise?
50%
Explain the synthesis of Epinephrin (adrenaline) from L-Tyrosine
(Incl intermediates and enzymes)
Dopamine is a ________ which is synthesised from ________ to L-Dopa via the enzyme ________.
L-Dopa is then converted into dopamine via the enzyme ________.
This occurs within ________ neurons.
Catecholamine, L-Tyrosine, Tyrosine Hydroxylase, DOPA decarboxylase, dopaminergic
In noradrenergic neurons dopamine is converted to Noradrenaline via the enzyme _______.
This can be furthur converted to Adrenaline within the cytosol of the adrenal gland via the enzyme _______.
Dopamine B-hydroxylase, Phenylethanolamine n-methyltransferase
Explain the 2 pathways in which dopamine can be degraded
(Incl intermediates and enzymes)
1) Dopamine ➞ 3,4 dihyrophenyl-acetic acid ➞ Homovanillic acid enzymes: monoamine oxidase, catechol-O-methyl transferase (COMT)
2) Dopamine ➞ Methoxytyramine (3MT) ➞ Homovanillic acid enzymes: COMT, monoamine oxidase
Give the 7 drug classes used in IPD
- Levodopa (L-DOPA)
- DOPA decarboxylase inhibitors
- Dopamine receptor agonists
- MAO type B inhibitors
- COMT inhibitors
- Anticholinergics
- Amantidine
Why can we not use dopamine itself to treat PD?
Cannot cross the BBB, use L-dopa (precursor) instead
Levodopa must be taken up by ________ cells in the ___________ to be converted to dopamine.
In PD we have _________ remaining cells, meaning there is a less reliable effect of levodopa. This can result in __________.
Once dopamine is produced the 2 enzymes _______ and ______ begin process of dopamine degredation.
dopaminergic, substantia nigra, fewer, motor fluctuations, MAO, COMT
State the following PK information about L-DOPA
- administration
- absorption mechanism
- T1/2
1) administration - ORAL
2) absorption mechanism - ACTIVE transport
3) T1/2 - 2 hrs
How much L-DOPA actually reaches the CNS and why?
90% inactivated in intestinal wall
9% converted to dopamine in peripheral tissues
<1% enters CNS
What is the implication of L-dopas administration AND transport mechanism?
Administration: as it is absorbed orally it must enter the GI system. Here 90% is inactivated within the intestinal wall by monoamine oxidase and DOPA decarboxylase
Transport: because it requires active transport, it competes with other large amino acids within the GI tract for space on transporters. This means high protein meals can reduce effectivness of L-DOPA.
What is the implication of L-DOPAs T1/2
As its half life is only 2 hours it requires short dose intervals (regular administration). This can result in fluctuations in blood levels producing motor symptoms.
What are the 2 types of movement produced by physiological dopamine and what is the effect of L-DOPA on these?
Physiologically dopamine is produces phasic relief (in response to an AP) and also tonic control (background level).
L-DOPA aims to mimic these actions by entering neurones however, it prodcues a certain amount of tonic movement due to its pre-mature beakdown before it is taken up into neurons.
Once L-DOPA reaches the BBB, what challenge does it face?
How can we overcome this pharmacologically?
Competition with other amino acids for active transport across blood brain barrier
Use L-DOPA in combination with a peripheral DOPA decarboxylase inhibitor
Give an example of a DOPA decarboxylase inhibitor
Give 2 examples of co-drug formulations of L-DOPA + the drug you have mentioned
DOPA decarboxylase inhibitor: carbidopa
L-DOPA + carbidopa:
- co-careldopa Sinemet
- co-beneldopa Madopar
Give 3 benefits of combining L-DOPA with a peripheral DOPA decarboxylase inhibitor
1) reduced dose required: because more is crossing the BBB
2) reduced side effects: less breakown of L-DOPA in the peripheries
3) Increased L-DOPA reaching brain
Give 3 tablet formations of L-DOPA
1) standard dosage – variable strengths
2) controlled release preparations (CR)
3) dispersible madopar (not soluble)
Give 2 advantages of L-DOPA
1) Highly efficacious
2) Low side effects
Give 4 potential side effects of L-Dopa
1) Nausea/ anorexia: vomiting centres
2) Hypotension: central and peripheral
3) Psychosis: schizophrenia-like effects: hallucination/delusion/ paranoia
4) Tachycardia
(But side effects are low)
Give 4 disadvantges of L-DOPA
Give 3 DDI’s with L-DOPA and the effect each has
1) Pyridoxine (Vit B6) ⬆ peripheral breakdown of L- DOPA
2) MAOIs risk hypertensive crisis (not MOABIs at normal dose-lose specificity at high dose)
3) many antipsychotic drugs block dopamine receptors: parkinsonism is a side effect
Why are Ergot derived dopamine receptor agonists no longer used?
Tendancy towards fibrosis of cardiac valves and lungs
Give 2 non-Ergot dopamine receptor agonists
Ropinirole and Pramipexole
Give an example of a dopamine receptor agonist that can be used as a patch
Rotigotine
Give an example of a dopamine receptor agonist that can be given subcutaneously
Apomorphine
Dopamine receptor agonists are usually used in what 2 ways?
Either De Novo therapy (starting therapy) or as add on therapy
What is Apomorphine?
A dopamine receptor agonist usually only used for patients with severe motor fluctuations
Give 3 advantages of Dopamine receptor agonists
Give 4 disadvantages of Dopamine receptor agonists
A side effect of dopamine receptor agonists is Impulse control disorders, give 4 examples of what this may include
Also known as Dopamine Dysregulation Syndrome
- Pathological Gambling
- Hypersexuality
- Compulsive Shopping
- Desire to increase dosage
- Punding
Give 4 symptomatic side effects of dopamine receptor agonists
- Sedation
- Hallucinations
- Confusion
- Nausea
- Hypotension
What is the role of Monoamine oxidase B?
Metabolises dopamine and Pre-dominates in dopamine containing regions in brain
What are the 2 enzymes which metabolise L-DOPA in the peripheries?
Incl the products of their metabolism
Dopa decarboxylase: L-DOPA ➞ dopamine
COMT: L-DOPA ➞ 3 O Methyldopa (competes with L-DOPA for transport across the BBB)
What is the function of MAOB inhibitors and give 2 examples
Function to enhance dopamine by prolonging the action of L-DOPA. Acts to smooth out motor response and can be used alone or as a adjunct therapy.
Eg. Selegiline and Rasagaline
(may be neuroprotective)
What does COMT stand for?
Catechol-O-methyl Transferase
What is the function of COMT inhibitors
Reduce peripheral breakdown of L-DOPA to 3-O-methyldopa ➞ as 3-O-methyldopa competes with L-DOPA for transport across the BBB, reducing its breakdownmeans less competition)
COMT inhibtors has no therapeutic effect alone so are used in combination tablets
What drugs are contained within these tablets, and give an example
COMT inhibitor, L-DOPA and peripheral dopa decarboxylase inhibitor
Eg. Stalevo
Give 2 benefits of COMT inhibtors
1) Have L-DOPA ‘sparing’ effect
2) As it prolongs the motor response to L-DOPA it reduces symptoms of ‘wearing off’
What is the use of Anticholinergics in PD
Give 2 examples
Acetyl Choline may have antagonistic effects to dopamine, has a minor role in treatment of PD
Eg.
- Trihexyphenidydyl
- Orphenadrine
- Procyclidine
Give 2 advantages of anti-cholinergics
1) Treat tremor
2) Not acting via dopamine systems
Give 2 disadvantages of anticholinergics
1) No effect on bradykinesia
2) Side effects (confusion, drowsiness, usual anticholinergic s/e)
What is the role of Amantidine is PD
It is a glutamate antagonist, hence will compete for binding with glutaminergic neurons.
However, there are no benefits or harms in the treatment of PD (but it is mentioned in NICE guidlines)
Watch this video if you get confused again
https://www.youtube.com/watch?v=Z84iypHdftQ
