PHARM - Drugs for the Treatment of Neurodegenerative Disease - Week 8 Flashcards
Define 6 characteristics of dementia.
Memory loss
Loss of logical thinking and judgement
Loss of speech and movements
Personality changes
Increased dependency for all needs
Decreased mobility to being bedridden
What is the most common form of dementia?
Alzheimer’s disease
What are two hallmarks of Alzheimer’s disease?
Beta-amyloid plaques and neurofibrillary tangles
Describe beta-amyloid plaques and where they accumulate.
Dense deposits of protein and cellular material that accumulate outside and around the nerves.
Describe neurofibrillary tangles.
Twisted fibres that build up inside nerve cells.
What is the precursor to beta-amyloid protein?
Amyloid precursor protein
Describe briefly in three steps how beta-amyloid plaques form.
Amyloid precursor protein sticks through the neuron membrane
Enzymes cut it into fragments of protein which include beta-amyloid
Beta-amyloid fragments clump together and form plaques
What do beta-amyloid plaques interfere with?
The work of neurons
Name the protein which provides the structural integrity for nerves, what protein they are supported by, and what happens to them in Alzheimer’s disease.
Neurons have an internal support partly made up of microtubules.
A protein called tau helps stabilise them.
In Alzheimer’s disease, they change and clump together to form neurofibrillary tangles.
The microtubules collapse.
Describe the cholinergic hypothesis for Alzheimer’s disease and a possible treatment option based on it.
Loss of ACh in Alzheimer’s correlates with impairment of memory - cholinergic deficiency contributes to cognitive decline.
Enhancement of cholinergic function stabilise or improve cognitive function and mat affect behaviour and daily functioning.
Name 4 behavioural symptoms that cholinergic deficiency may contribute to in Alzheimer’s disease.
Psycosis-agitation
Apathy-indifference
Disinhibition
Aberrant motor behaviour
In what severity of Alzheimer’s do cholinesterase inhibitors have efficacy?
Mild/moderate
What class of drugs used to treat Alzheimer’s may be helpful for Lewy body disease?
Cholinesterase inhibitors
How do cholinesterase inhibitors work?
They decrease ACh breakdown
Name 16 adverse effects of cholinesterase inhibitors.
Nausea
Vomiting
Diarrhoea
Anorexia
Abdominal pain
Headache
Insomnia
Vivid dreams
Depression
Fatigue
Drowsiness
Dizziness
Urinary incontinence
Increased sweating
Tremor
Muscle cramps
Does treatment of Alzheimer’s with cholinesterase inhibitors prevent cognitive decline?
Initially it may, however eventually cognitive decline will decline at the same rate as without treatment.
However, cognitive state with treatment will still be higher than if there was no treatment.
In other words, it transiently maintains cognitive abilities.
Describe the action of γ secretase.
Cleaves the amyloid precursor protein with its transmembrane segment
What is presenilin and what does it affect? What happens with a mutation to this protein?
It is a component of the γ secretase complex.
It affects APP processing.
If mutated, there is an increase in amyloid beta fragments.
Briefly describe the concept of anti-amyloid immunotherapy for Alzheimer’s treatment.
Subjects are immunised with beta amyloid and attenuates Alzheimer’s disease-like pathology
Do anti-amyloid drugs work?
Some studies suggest no.
What is the accumulation of beta amyloid linked to?
Degenerative changes in the brain.
Name three aims of Alzheimer’s disease therapy.
Improve cognitive function
Limit disease progression
Symptom control
Describe Parkinson’s disease.
A chronic, progressive neurodegenerative disease of muscle movement
Describe the pathology of Parkinson’s disease.
Degeneration of the dopaminergic neurons in the substantia nigra pars compacta
Levels of which neurotransmitter decreases in Parkinson’s?
Dopamine
What can be identified in the brains of individuals with Parkinson’s post-mortem?
Lewy bodies
Name 7 motor signs and symptoms of Parkinson’s.
Tremors
Rigidity of limbs
Bradykinesia
Impairment of postural reflexes
Facial - impassive, no blinking
Speech - monotonous, hypnophonic
Decreased manual dexterity
Name 9 non-motor signs and symptoms of Parkinson’s.
Cognitive deficiencies
Depression
Raised anxiety levels
Olfactory deficiencies
Sleep disturbances
Fatigue
Pain
Bowel and bladder problems
Sexual dysfunction
Why do dopamine levels decrease in Parkinson’s?
Dopaminergic nerves in the substantia nigra degenerate, reducing dopamine levels
How do Lewy bodies form?
Dopamine is oxidised which results in the misfolding and accumulation of a-synuclein.
Name three main management therapies for Parkinson’s.
Drugs that provide symptomatic relief - palliative rather than curative
Restore dopamine deficiency
Restore dopaminergic/cholinergic balance in the striatum
Name four ways dopamine deficiency can be restored in Parkinson’s.
Increase dopamine synthesis
Increase dopamine release
Dopamine receptor agonists
Reduce dopamine metabolism
How can dopaminergic/cholinergic balance in the striatum be restored?
Cholinergic antagonists
Does dopamine cross the blood brain barrier?
No
Is there neuronal uptake of dopamine from the synapse? What about extraneuronal uptake?
Yes to both
What is dopamine a precursor to?
Noradrenaline
Name and describe a drug that can increase dopamine synthesis,
Levodopa - an amino acid isomer
Where is lveodopa mostly metabolised?
In the periphery
What is levodopa formulated with?
peripheral dopa decarboxylase inhibitor
What dose is required for levodopa, large or small?
Large doses required
What happens to levodopa in the periphery?
Converted to dopamine and noradrenaline
Name 4 side effects of levodopa.
Nausea
Vomiting
Orthostatic hypotension
Cardiac dysrhythmia
What does levodopa require?
Some functional dopaminergic neurons
What drug is the first line of treatment for Parkinson’s?
Levodopa
What two main symptoms does levodopa help reduce?
Rigidity and tremors, among others
When does rapid absorption of levodopa occur?
Empty stomach
What two amino acids compete with levodopa uptake?
Leucine and isoleucine
What happens to the effectiveness of levodopa with time and why? What is done in these cases?
Declines with time due to the continued degeneration of dopaminergic nerves.
Dose is increased or incorporated with other drugs.
Name an ocular side effect of levodopa.
Pupil dilation
In patients with which ocular disease should levodopa be avoided?
Glaucoma
Can levodopa cause hallucinations?
Yesd
Name four drug interactions with levodopa.
Vitamin B6
MAO inhibitors
Inhalational anaesthetics
Anticonvulsants and neuroleptics
What kind of drug is preferred in younger patients for treating Parkinson’s?
Dopamine agonists
Name two examples of dopamine agonists.
Bromocriptine and cabergoline
Name some side effects of dopamine agonists (5).
Same as levodopa, but hallucinations, confusion, delirium, nausea, and hypotension more common
Name a severe side effect of dopamine agonists.
Myocardial infarction
What effect do MAO inhibitors have? Give an example.
MAO breaks down dopamine, so increased levels of dopamine
Selergine
What is the effect of COMT inhibitors? Give an example.
Reduces the metabolism of L-dopa
Entacapone
What is amantadine normally used for and what does it do in regards to Parkinson’s treatment?
Antiviral for influenza
Enhances release of dopamine
Does amantadine have a slow or rapid tolerance?
Rapid
What effect does amantadine have on cholinergic activity?
Anticholinergic activity
Name 7 side effects of amantadine.
Restlessness
Agitation
Confusion
Hallucination
Orthostatic hypotension
Urinary retention
Dry mouth
Do muscarinic receptor antagonists have a strong or modest effect on tremors and rigidity?
Modest
Describe how adenoside A2a receptor antagonists work.
They interact with a specific subtype of dopamine receptors making it more sensitive to dopamine, boosting the effects of L-DOPA.
Describe how reducing glutamate levels may be used to help treat Parkinson’s, including the receptor targetted.
mGluR5 receptor is targetted, allows for using higher doses of L-Dopa.
What two things about a-synuclein may cause Parkinson’s? What sizes are believed to be the real drivers?
Mutating or overproducing a-synuclein.
Small oligomers and not larger fibrils are the real toxic drivers of the disease.
Can mitochondrial dysfunction cause Parkinson’s?
Yes, by releasing harmful oxygen-based molecules
Do cigarette smoking and coffee drinking increase the risk of Parkinson’s?
No, quite the opposite.
No one knows why either would be protective.
Are pesticides linked with Parkinson’s?
Yes
Are herbicides linked with Parkinson’s?
No (at least not by lecture material)
Which parts of the brain connected to what two regions of the body are the first to be affected in Parkinson’s? What does this suggest?
Parts of the brain that connect to the gut and the nose.
This suggests environmental exposure to toxins or infectious agents can trigger the disease.
Is dopamine highly reactive or neutral?
Highly reactive
What can oxidised dopamine enhance the stability of?
a-synuclein oligomers.
What is the clearest risk factor for Parkinson’s? Why is this so (2)?
Ageing
Possibly due to the weakening of mitochondria and reducing the neuron’s ability to dispose of harmful a-synuclein aggregates
What does MPTP do and what does it cause as a consequence?
Depletes dopamine terminals and causes Parkinson’s disease symptoms
Is MPTP lipid-soluble? Can it cross the blood brain barrier?
Yes to both
What neuron does MPTP enter, what is it converted to, and by what? What happens as a result (2)?
Enters astrocytes, and is converted to toxic MPP+ by MAO-B
It accumulates in the mitochondria of dopaminergic cells, resulting in energy depletion and death.
