Parkinson's Disease Flashcards
What is Parkinson’s disease?
A degenerative condition caused by the loss of dopamine-secreting neurons in the midbrain area of the substantia nigra causing tremor and impairment.
It is progressive due to death of dopaminergic neurones as well as presence of Lewy Bodies
What are the main functions of DA?
Memory
Movement
Motivation
Mood
Learning
Sleep
Attention
Good behaviour
Thinking
What is the purpose of Lewy Bodies?
Disruption of neurotransmitter balance and loss of connection between nerves and ultimately destruction of dopamine.
If something attacks substantia nigra what are the symptoms?
Tremors and moto impairment
Where is DA released/contained from?
Substantia nigra
DA released from nucleus accumbens and hippocampus normally functions with?
Pleasure
DA released from substantia nigra normally functions as?
Motor function & memory
What are the three areas that DA can be released from?
Substantia nigra, nucleus accumbens & hippocampus
If DA drops then ACh what?
Increase vice versa
3 Functions of DA?
Voluntary movement
Produces Neurotransmitter DA
Regulates mood
What are motor and non-motor symptoms of parkinsons?
Motor - Bradykinesia - slow movement
Hypokinesia - delayed action
Stiffness & rigidity
Rest tremor due to increase of ACh
Non-motor - Depression - DA = pleasure - decrease will decrease happiness
Also due to reduced movement which is depressing
Reduced cognitive impairment
Diagnose parkinsons?
Take a med history and physical examination
Within examination monitor motor function and also if there was a positive response to Levodopa
CT & PET - not useful
Biomarkers in urine, blood and CSF - not useful
Is PD linked to aging?
No
What is the ideal of clinical management for PD?
To restore DA & ACh levels
No cure so aim to slow deterioration
What are 4 drug functions used to manage PD?
Replace DA
Inhibit ACh
Mimic role of DA
Prevent destruction of DA/ Allow reuptake of DA
What are the three main treatments of early stages of PD? & THEIR DRUG TYPE
Levodopa - precursor of dopamine
Oral/transdermal NON ERGOT dopamine agonists - stimulate release of DA from substantia nigra
Monoamine-oxidase-B inhibitors - ACh inhibitor
What is the cheese interaction?
Patient on MAOI means increased levels of tyramine which is vasoconstrictive. Cheese contains tyramine resulting in hypertensive crisis
Why don’t you start pt on Levodopa?
Can develop resistance so preserve this as another stage of treatment (most effective treatment)
Start with DA Agonist
Why can Levodopa cross BBB?
Lipophilic & small
Why is levodopa given as a combo rather than on its own?
Levodopa can cross BBB. It is a prodrug meaning it needs activation - we require these to be in the brain not the periphery.
These enzymes are - Dopa decarboxylase - breakdown levodopa to da in the peripheral system meaning they can’t cross BBB and work in CNS.
Combination of levodopa and enzyme inhibitors to inhibit peripheral metabolism of levodopa to dopamine & allow levodopa to cross BBB and be converted to DA in central. It also means you are giving pt lowest dose - reduces adverse effects & increase therapeutic effect
What are the three LD enzymes that breakdown L-dopa to DA?
COMT -p&c
DD - DOPA DECARBOXYLASE - p&c
MAO- c only
What does carbidopa do?
Protective enzyme which acts on DD and allows DA to cross BBB
What are the two main examples of peripheral dopa-decarboxylase inhibitors? When are these given?
Carbidopa & Benserazide
Later stage treatments
Why is a lower dose of Levodopa administered when in conjunction with carbidopa or benserazide?
These inhibit peripheral conversion of Levodopa to DA - therefore more can cross BBB
What happens to levodopa once it crosses the BBB?
Broken down by dopa decarboxylase into DA and stored in nigrostriatal nerve terminals
What is Levodopa with Benserazide?
Co-Beneldopa = Madopar
What is Levodopa with Carbidopa?
Co-Careldopa = Sinemet
Symptoms of DA in periphery
Vomiting Nausea & postural hypertension
What is the first line treatment of Parkinson’s?
Examples
Dopamine agonists - Non ergot derived (specifically)
Non-Ergot - Pramipexole, Ropinirole & Rotigotine
Why are Ergot Derived Dopamine agonists not used?
Severe side effects in lungs and hrt
- Cabergoline & Pergolide
Which to start with DA agonist or Levodopa in early stages?
DA Agonist as Levodopa can improve symptoms rapidly but also causes resistance in prolonged use. This causes a rapid improvement followed by a rapid decline. By constantly increasing the dose of L-dopa - side effects increase.
DA Agonists have many advantages as they act directly on DA receptors
They don’t require conversion to form the active product - no issue with metabolic enzymes
DA Agonists have a longer half life
DA Agonists are associated with less motor side effects such as dyskinesias
topical or patches
Side effects of ergot derived DA
Pleural fibrosis
Two fold to four fold increased risk for cardiac valve fibrosis when compared to non-ergot derived
What is the Mechanism of action and examples of MAO-B inhibitors?
Side effects & Withdrawal symptoms?
They promote reuptake of DA by decreasing the breakdown of DA in the striatum.
Examples - Selegiline and Rasagiline
Considered a first line treatment
Selegiline has side effects - hallucinations, insomnia & confusion
Selegiline when during withdrawal = causes deteriorated motor function
What is the Mechanism of action and examples of MAO-B inhibitors?
Side effects & Withdrawal symptoms?
They promote reuptake of DA by decreasing the breakdown of DA in the striatum.
Examples - Selegiline and Rasagiline
Considered a first line treatment
Selegiline has side effects - hallucinations, insomnia & confusion
Selegiline when during withdrawal = causes reduced motor function
What are the MAO of COMT inhibitors?
What line of treatment?
Prevent the conversion of L-dopa to DA in periphery.
Second line therapy. Must be given alongside L-dopa
Example - Tolcapone
What is a side effect of tolcapone?
Hepatotoxicity
Why are antimuscarinics used in Parkinson’s
Younger patients with severe tremor and dystonia which is painful muscle movements
Work by inhibit ACh level restoring DA balance
Late stage
Procycline
Why would amantadine be coprescribed?
An antiviral to help aid L-dopa induced dyskinesia - cuncontrolled muscle twitching
Works by facilitating presynaptic DA release
Blocking DA reuptake - anticholinergic effect
What are last line therapy for parkinson’s?
Pallative care - Duodopa
Apomorphine
Deep brain stimulation - to still function substantial nigra cells to promote DA release
What is a risk of interrupting therapy for parkinson’s?
Neuroleptic Malignant Syndrome - if therapy is stopped
Tachycardia
Epileptic Seizures
As parkinson’s disease progresses?
Increase drug dose
Shorten intervals between doses
Drug combinations
Look at slide 66
What is drug induced parkinsons disease?
When a patient has been on a drug for prolonged period of time and it has caused muscular rigidity
A pronounced tremor in limbs and jaw
Difficulty walking - Not due to permanent damage so may last for 2 yrs
What drugs can induce Parkinson’s
Antipsychotics - Chlorpromazine
Anti-emetics - cyclizine
What are two surgery methods to treat parkinsons?
Pallidotomy - Help with dyskinesia - destroys internal globus pallidus
Thalamotomy - Treat severe tremor - destroys thalamus
