Session 13: Neurology Flashcards
Clinical features of parkinsonism.
Tremor
Rigidity
Bradykinesia
Postural instability
Non-motor manifestations of PD
Mood changes
Pain
Cognitive changes
Urinary symptoms
Sleep disorder
Sweating
Features of parkinson down the line after 15 year follow up.
Dyskinesia
Falls
Cognitive decline
Somnolence
Swallowing difficulties
Severe speech problems
DDx of idiopathic parkinson’s disease.
Drug induced parkinsonism
Vascular parkinsonism
Progressive supranuclear palsy
Multiple systems atrophy
Corticobasal degeneration
Pathophysiologt of IPD.
Neurodegeneration with Lewy bodies present.
There is a loss of pigment of the substantia nigra (50% loss leads to symptoms)
There is an increased turnover and and upregulation of receptors.
Reduction of dopamine
Explain the catecholamine synthesis pathway of dopamine.
L-Tyrosine -> L-DOPA - (DOPA decarboxylase) > Dopamine -> Noradrenaline -> Adrenaline
Explain the dopamine degradation.
Dopamine is converted to an acetic acid or 3-MT via monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT).
These products are then converted into homovanillic acid by MAO or COMT again.
Explain the transport of neurotransmitters.
Synthesis of neurotransmitters and formation of vesicles happen in the soma of the neuron. They are then transported down the axon to the presynaptic terminal.
An action potential then causes calcium to enter the presynaptic terminal and there is a release of neurotransmitters as calcium binds to the vesicles.
NT attaches to a receptor and either excites or inhibits.
NT dissociates and is either degraded or taken up again by the synaptic cleft and recycled.
Give an example of a scan used in IPD.
DAT scan
It records the presynaptic uptake and will be abnormal in PD.
However it is not diagnostic.
Why is Parkinson’s not treated with dopamine?
Because dopamine cannot cross the blood-brain barrier.
Give examples of drugs used in Parkinson’s.
Levodopa (L-DOPA)
Dopamine receptor agonists
MAOI type B inhibitors
COMT inhibitors
Anticholinergics
Amantidine
How does levodopa rely on the dopaminergic cell in the substantia nigra?
Levodopa must be taken up by the dopaminergic cells in order to be converted into dopamine.
This means that fewer remaining cells -> less reliable effect of levodopa and motor symptoms will become less sedated.
Pharmacokinetics of levodopa.
Oral admin
Absorbed by active transport and 90% of it is inactivated in the intestinal wall. This is by MAO and dopa decarboxylase.
Half-life of 2 hours meaning there is a short dose interval and fluctuations in blood levels and symptoms.
9% converted to dopamine in peripheral tissues by DOPA decarboxylase (AADC)
This means that less then 1% will enter the CNS.
If less than 1% of levodopa will enter the CNS, how is it effective?
Because you also give a DOPA decarboxylase inhibitor (AADCi) with the levodopa.
The DOPA decarboxylase inhibitor cannot pass the BBB so it only inhibits the conversion of levodopa to dopamine in the periphery and not in the CNS.
Give examples of DOPA decarboxylase inhibitors.
Usually come in a combination with the levodopa such as co-careldopa (Sinemet) and co-beneldopa (Madopar)
Benefits of combination therapy of levodopa and DOPA decarboxylase inhibitor.
Reduced dose required
Reduced side effects
Increased levodopa reaching the brain
Advantages of L-DOPA
Highly efficacious and low side effects.
Give ADRs of levodopa.
Nausea and anorexia as it targets the vomiting centres
Hypotension
Psychosis
Tachycardia
Disadvantages of levodopa
Needs enzyme conversion to be active
Long term effects as the levodopa will start to wear off.
There is a loss of efficacy as the dopaminergic neurones will die.
There are involuntary movements and motor complications.
Give examples of motor complications of long term levodopa administration.
On/off freezing in place
Dyskinesias
Dystonia
Freezing
DDIs of levodopa
Vitamin B6 increases peripheral breakdown of levodopa.
When administered with MAOIs there is a risk of hypertensive crisis.
Many antipsychotic drugs block dopamine receptors and parkinsonism is a side effect.
Give examples of dopamine receptor agonists.
Non-ergo such as ropinirole and pramipexole
When are dopamine receptor agonists used?
As de novo therapy or as an add on therapy.
Advantages of dopamine receptor agonists.
Direct acting
Less dyskinesias and motor complications
Possible neuroprotection
Disadvantages of dopamine receptor agonists.
Less efficacy than L-DOPA
Impulse control disorders might manifest
More psychiatric side-effects
Expensive
Give examples of impulse control disorders that might manifest as side effects of dopamine receptor agonists.
Pathological gambling
Hypersexuality
Compulsive shopping
Desire to increase the dosage due to ‘rewarding nature of drug’.
Punding
Give ADRs of dopamine receptor agonists.
Sedation
Hallucinations
Confusion
Nausea
Hypotension
Explain the action of monoamine oxidase B inhibitors (MAOis)
Monoamine oxidase B metabolises dopamine.
This means that an inhibitor will enhance dopamine.
Give examples of monoamine oxidase B inhibitors.
Selegiline
Rasagaline
Can MAO inhibitors be used alone?
Yes they can
They prolong the action of levodopa and smooths out motor response.
It may also be neuroprotective.
Explain the mechanism of action of COMT inhibitors.
Reduce the peripheral breakdown of L-DOPA to 3-O-methyldopa.
This is important as 3-O-methyldopa will compete with L-DOPA active transport into CNS.
Less 3-O-methyldopa means more L-DOPA can cross the BBB.
Give examples of COMT inhibitors.
Entacapone which doesn’t cross the BBB
Tolcapone which crosses the BBB but main effect is peripheral
Can COMT inhibitors be given alone?
No, they are no therapeutic effect alone
When are COMT-inhibitors given then?
In combination with L dopa and peripheral dopa decarboxilase inibitor (Stalevo)
Advantages of COMT inhibitors.
They have an L-DOPA sparing effect and prolongs the motor response to L-DOPA and reduces the symptoms of wearing off.
Explain why anticholinergics might be used in IPD.
May have an antagonistic effect to dopamine.
Advantages of anticholinergics in IPD.
Treats the tremor and don’t act via the dopamine systems.
Disadvantages of anticholinergics in treatement of IPD.
No effect on bradykinesia
Side effects such as confusion, drowsiness and other anticholinergic side effects.
Explain mechanism of action of amantadine.
Uncertain but possible enhanced dopamine release and anticholinergic NDMA inhibition.
It is not really used anymore
If all medications fail, what is suggested as the next intervention?
Apomorphine or surgery such as deep brain stimulation.
Clinical features of myasthenia gravis.
Fluctuating, fatigueable, weakness of the skeletal muscles.
The most common presentation is of the extraocular muscles.
There is also bulbar involvement leading to dysphagia, dysphonia and dysarthria.
Limb weakness
Respiratory muscle involvement.
Give examples of drugs affecting the neuromuscular transmission that will exacerbate Myasthenia gravis.
Aminoglycosides
Beta-blockers, CCBs, quinidine and procainamide.
Chloroquine and penicillamine
Succinylcholine
Magnesium
ACE inhibitors
Complications of myasthenia gravis.
Acute exacerbation -> myasthenic crisis
Overtreatment -> cholinergic crisis
Explain the action of ACh esterase inhibitors.
Enhance the neuromuscular transmission by inhibiting the breakdown of acetylcholine.
This happens in both skeletal and smooth muscle.
Explain cholinergic crisis.
If an excess dose is taken which can happen in MG because as they take the medication they might feel better and want to take more.
An excess dose can cause a depolarising block.
Give examples of ACh esterase inhibitors.
Pyridostigmine taken orally
Neostigmine take oral or IV
Cholinergic side effects of pyridostigmine.
SSLUDGE
Salivation
Sweating
Lacrimation
Urinary incontinence
Diarrhoea
GI Upset and hypermotility
Emesis
