Drugs to treat neuro-degeneration Flashcards
What are neurodegenerative diseases?
these are incurable and debilitating conditions that result in the progressive degeneration or death of neurones (chronic)
Dead neurones in the adult CNS are replaced and their terminals can regenerate when their axons are interrupted. True or false
False
Pathological processes causing neuronal cell death can be described as having ____________ consequences.
irreversible
What has lead to the increase in research activity for neurodegenerative diseases ?
Incidence and social impact
What is the future of drug therapy in neurodegenerative disease?
Regenerative stem cell therapies to replace lost neurons
How are proteins in neurodegenerative diseases affected?
mis-folding of normal physiological proteins
mutated forms of physiological proteins
Briefly describe how mis-folded proteins are removed by intracellular degradation pathways
Chaperone proteins are produced; they binds to newly synthesised misfolded proteins and encourage them to fold correctly
Ubiquitination is also another intracellular process which marks proteins for degradation
What is a characteristic of mis-folded proteins ? What encourages this characteristic?
They tend to aggregate
This is because mis-folded proteins present hydrophobic surface residues; this promotes aggregation
Mis-folded proteins initially exist in what form?
Soluble oligomers
Mis-folded proteins later exist in what form?
insoluble aggregates
Insoluble aggregates of mis-folded proteins accumulate as ____________ intracellularly and extracellularly.
microscopic deposits
Insoluble aggregates are stable and resistant to proteolysis because…
Protective degradation mechanism is unable to cope
There is evidence that suggests that both soluble an insoluble aggregates may be neurotoxic. True or false
True
Excitotoxicity and free radical production lead to _________ and ___________.
Mitochondrial damage
Calcium overload
The NMDA receptor has a ____________ block.
magnesium
What are the glutamate receptors?
AMPA and NMDA receptors
What is the effect of an AMPA receptor on NMDA receptor in the presence of a strong stimulus ?
The magnesium block is displaced
Na+ and large Ca2+ ions can diffuse intracellularly via NMDA channel
Activation of glutamate receptors causes …
A calcium overload
Calcium influx
Calcium overloads affect many processes that are related to neurotoxicity. Give examples of instances where Ca2+ overloads affect neurotoxicity
-increased glutamate release from nerve terminals
-activation of proteases (e.g. calpains) and lipases which can cause membrane damage
-mitochondrial calcium overload stimulates the production of ROS
-activation of nitric oxide synthase which generates NO
-increased AA release and expression of COX results in the release of inflammatory mediators (PGs) and ROS as a byproduct of peroxidase activity of COX
What is the cyclooxygenase activity of COX enzyme ?
oxygenates AA to PGG2
What is the peroxidase activity of COX enzyme ?
reduces PGG2 to PGH2
What is the effect of free radicals on cells?
Damage mitochondria, membrane lipids, protein and DNA
What is produces when concentration of NO is high in the presence of ROS?
A highly reactive peroxynitrite free radical (ONOO-)
What is the effect of ROS on the mitochondria?
- inhibition of oxidative phosphorylation and reduced ATP synthesis which causes Ca2+ pump to stop working; this prevents Ca2+ sequestrations/extrusion mechanisms
- mitochondrial damage causes release of cytochrome C into cytosol initiating apoptosis
What is the potential effect of mitochondrial ROS such as superoxide?
O2- reacts with NO to form peroxynitrite (ONOO-)
What leads to neuronal cell death?
combination of excitotoxicity, calcium overload, free radicals, mitochondrial damage and oxidative stress
What is oxidative stress?
imbalance between the production of damaging ROS and antioxidant defences
Give examples of physiological antioxidant defences?
- superoxidde dismutase (SOD)
- catalase
- ascorbic acid
- glutathione (paracetamol?)
What neurological conditions have drugs available for treatment?
Parkinsons
Alzheimers
Huntingtons
Ischaemic brain damage
Neuropathic pain
What is parkinsons disease?
Progressive neurodegenerative disorder affecting the motor system
What are the cardinal signs of parkinsons disease?
Tremors: often begins in hand, foot and jaw
Rigidity (muscular): resistance to movement or short jerky movements
Bradykinesia: slow movement, loss of spontaneous/automatic movement
Postural instability: lack of balance and coordination
Describe briefly the pill-rolling tremor in hands observed in PD
- forefinger and thumb rub together (as if rolling a pill between them)
- slight wrist flexion and extension (up and down)
What is a shuffling gait?
- difficult to start walking
- in progress difficult to stop or change direction
What are the cognitive and psychiatric symptoms of PD ?
Depression and anxiety
Dementia
Behavioural problems
List some non-motor symptoms of PD?
Loss of sense of smell
Neuropathic pain
Problems with urination
Constipation
Postural hypotension
Excessive sweating
Swallowing difficulties
Drooling (sialorrhoea)
Sleeping disorders
What are the types of parkinsons disease?
Idiopathic PD
Familial PD
Vascular Parkinsonism
Drug induced Parkinsonism
Causes of idiopathic PD are unknown. What factors can affect idiopathic PD
genetic
environmental- exposure to pesticides, history of head injuries
How is early onset idiopathic PD described?
<50 years old
How is late onset idiopathic PD described?
> 50 years old
What known genes are implicated in familial PD?
LRRK2
PARK7
PINK1
PRKN
SNCA
Vascular parkinsonism can be caused by …
restricted blood supply to the brain
Mild stroke
Give an example of drug-induced parkinsonism
Antipsychotic drugs which block the action of dopamine
What proteins are implicated in alzheimers disease and what it the characteristic pathology?
Beta-amyloid- amyloid plaques
Tau protein- neurofibrillary tangles
What proteins are implicated in PD and what is the characteristic pathology?
alpha- synuclein - Lewy bodies
What proteins are implicated in Creuzfeldt-Jakob disease and what is the characteristic pathology ?
Prion protein- insoluble aggregates of prion protein
What proteins are implicated in Huntingtons disease and what is the characteristic pathology ?
Huntingtin- there are no gross lesions
What proteins are implicated in Motor Neuron disease and what is the characteristic pathology ?
Superoxide dimutase (antioxidant defence); loss of motor neurons
What is the aetiology of PD
loss of pigmented cell (dopaminergic neurons) in the substantia nigra (SN is part of the basal ganglia which is concerned with reward and movement)
cells contain atypical eopsinophilic inclusions in cytoplasm (lewy bodies)
What is the primary component of lewy bodies?
abnormal aggregates of alpha synuclein protein
What are the functional parts of the basal ganglia?
Striatum
Pallidum
Thalamus
Subthalamic Nucleus
Substantia Nigra
What components are part of the striatum in the basal ganglia ?
Caudate nucleus
Putamen
What are the components of the pallidum?
Globus pallidus external
Globus pallidus internal
What is a nuclei (CNS)?
A cluster of neurons in the CNS located deep within the cerebral hemisphere and brain stem
What are the pathways of the basal ganglia ?
Direct and indirect pathways
The direct pathway is __________ whilst the indirect pathway is ________ (voluntary movement)
Excitatory
Inhibitory
Describe the direct pathway of the basal ganglia
Glutamate is released from cortex into striatum
Striatum is then stimulated to release GABA NT
The GABA NT acts on the Globus pallidus internal and prevents it from releasing its own GABA NT which would otherwise inhibit the thalamus
The thalamus is therefore free to release glutamate to cortical motor areas and thus movement is not suppressed
What modifies the activity of the direct pathway, how does it do so?
Substantia Nigra par compacta
Neurones from SNc travel to the striatum via the nigrastriatal pahway and release dopamine into the striatum
Dopamine excites the striatal cells and turn UP motor activity - striatal cell are encouraged to release more GABA and allow thalamus to stimulate cortical motor areas
What is the effect of cholinergic neurones in the striatum?
They release ACh
ACh has an inhibitory effect on striatal cells and thus GABA is not released to stop globus pallidus internal from exerting inhibitory effect on thalamus
ACh therefore has an inhibitory effect on movement
ACh inhibits striatal cells in the direct loop
Describe the indirect pathway of the basal ganglia
Glutamate is released from cortex and stimulates striatal cells to release GABA
This stops the globus pallidus external from releasing GABA to inhibit the action of the subthalamic nucleus
Thus the subthalamic nucleus can relesae glutamate which stimulated neurones in the globus pallidus internal
Globus pallidus internal therefore releases GABA which stops activation of the thalamus therefore the thalamus does not send signals to cortical motor areas hence no unwanted movement occurs
What is the main function of the direct pathway?
Turn UP motor activity
What is the main function of the indirect pathway?
Turn DOWN motor activity
What is the function of cholinergic neurones in the indirect pathway?
stimulation of the striatal cells
causes release of GABA which inhibits globus pallidus external
This means STN is free to stimulate globus pallidus internal and thus the inhibition of thalamus
ACh excites striatal cells in the indirect loop
The thalamus is referred to as…
The relay centre
What is the function of dopaminergic neurones in the indirect pathway?
Inhibits neurones in the indirect loop and therefore STN is inhibited and the globus pallidus internal is inhibited and motor activity increases
What is the effect of PD on the direct pathway?
A decrease in dopamine causes a decrease in the direct pathway
This means that ACh inhibition is unopposed
Therefore no GABA is not released to inhibit the globus pallidus and there is less motor activity
Less motor activity leads to bradykinesia (slow movement)
What is the effect of PD on the indirect pathway?
There is less dopamine which leads to an increase in the indirect pathway
This means that there is a dopamine inhibition loss
ACh excitation is unopposed and globus pallidus external is inhibited therefore STN is free to stimulate globus pallidus internal which inhibits action of the thalamus
This also leads to less motor activity
Bradykinesia (slow movement)
Give examples of methods that can be used to treat PD
Elevating regional dopamine levels (levodopa, MAOBIs, COMT inhibitors)
Stimulating dopamine receptors (DA agonists)
Inhibiting the effect of cholinergic afferents (ACh antagonists)
Inhibiting glutaminergic NMDA receptors (amantadine)
MAO stands for …
Monoamine oxidase
They can metabolise dopamine
What is the function of MAO-I
they are effective antidepressants especially for the treatment of resistant depression and atypical depression
Give examples of COMT inhibitors
Tolcapone
Entacapone
What is COMT and where are they found?
They are found in surrounding glial cells
Stands for catechol-o-methyl transferase
COMT enzyme that degrades L-DOPA
L-DOPA is the dopamine ________ and is described as a _______ therapeutic
precursor
short-acting
Which type of dopamine precursor can cross the BBB?
L-DOPA
What type of dopamine precursor cannot cross the BBB?
Carbidopa
What is the function of carbidopa when administered with L-DOPA?
inhibitor of peripheral DOPA decarboxylase
What is the function of DOPA decarboxylase?
convert L-DOPA into dopamine
What is the advantage of the addition of carbidopa?
it minimises the dopamine-induced side effects
it increases levels of L-dopa reaching the brain (as it does cross BBB)
What is the function of COMT inhibitors?
reduce metabolism of L-DOPA and dopamine peripherally or centrally increasing levels reaching the brain
Give examples of selective MAO-B inhibitors. State their function
Selegiline
Rasagiline
Prevent metabolism of dopamine centrally
What are the acute side effects of L-DOPA
Nausea and vomiting
Postural hypertension
How can you combat acute side effects of L-DOPA such as nausea and vomiting?
Use anti-emetic (domperidone)
What are slow developing side effects of L-DOPA?
involuntary movements (dyskinesia)
on- off effect (bradykinesia)
Plasma L-DOPA fluctuations
Give examples of dopamine agonists used to treat PD
Bromocriptine
Pramipexole
Ropinirole
Rotigotine
Apomorphine
What are the side effects of Bromocriptine (DA agonist)
Nausea and vomiting
risk of fibrotic reactions in the lungs, retroperitoneum and pericardium
Rorigotine (DA agonist) is delivered via …
Transdermal patch
What are the side effects of rotigotine?
Impulse control disorders e.g. pathological gambling, binge eating and hypersexuality
Apomorphine is delivered via…
Subcutaneous injection
What are the side effects of apomorphine?
powerful emetic action (vomiting)
Give an example of a ACh antagonist used to treat PD
Orphenadrine
What are the side effects of orphenadrine
dry mouth
impaired vision
constipation
urinary retention
(remember basically blocks rest and digest; paramsympathetic action)
Orphenadrine is used to treat…
drug induced extrapyramidal symptoms (parkinsonism)
Difference between PD and parkinsonism
PD is caused by neurodegeneration (in the brain) whilst the causes of parkinsonism are numerous
Briefly state this history of the drug Amantadine
First introduced as an antiviral drug, discovered to be beneficial in PD by accident in 1969
Amantadine is more effective than L-DOPA and dopamine agonists in treating PD. True or false
False
Less effective
What are the proposed MOAs of Amantadine
- on the pre-synaptic membrane, enhances dopamine release and inhibits its reuptake
- on post-synaptic membrane, acts directly on the dopamine receptors
- anti-glutamatergic properties, via non competitive antagonism of NMDA receptors - reduced the severity of L-DOPA induced dyskinesia (unwanted movement)
What is non-competitive antagonism?
Antagonist binds to the allosteric site of the receptor or binds irreversibly to the active site of the receptor
What drugs is contraindicated when using COMT and MAO-B inhibitors? What is the interaction
Adrenaline
Increased risk of cardiovascular side effects
Increase risk of hypertensive crisis
What drug is contraindicated when using DA agonist bromocroptine? State the interaction
Erythromycin
May increase exposure to bromocriptine
What drug is contraindicated when using MAO-B inhibitors? State the interaction
Pethidine
Concurrent use can increase the risk of serotonin syndrome
List symptoms of serotonin syndrome
High body temperature
Agitation
Increased reflexes
Tremor
Sweating
Dilated pupils
Diarrhoea
Seizures
List some dental considerations that must be taken into account when treating patients with PD
-schedule appts when medication is working best, with a care giver present
- mask- like expression means patients lack non-verbal communication. Verbal comms is also slow, take more time to treat the pt; make use of yes/no questions and observe pt carefully during procedure for signs of pain
-there is also anxiety linked with increased tremors (may affect tongue, lips), try to reduce stress of patient, be careful with sharp instruments
-dental chair should NOT be reclined more than 45 degrees to avoid swallowing reflex of saliva, fluids and debris; can cause aspiration pneumonia
-at the end of the treatment, chair should be raised slowly to avoid problems with loss of balance or postural hypotension
What are the dental risks associated with xerostomia (dry mouth)?
Increased risk of caries, periodontal disease, poor denture retention, oral discomfort
What are the dental considerations that you should consider for a patient on Levodopa medication?
Burning mouth association
Oral discomfort
List some other oral health considerations you must consider for patients with PD
Motor impairments, struggling to brush their teeth; increased caries risk; consider use of electric toothbrush
Dysphagia, pooling, can cause aspiration pneumonia
Dentures, muscle incoordination rigid facial muscles and xerostomia of PD can jeopardise retention and control
Alzheimers is a common _____ related dementia
Age
(>65 years old)
What is alzheimers disease ?
memory loss and difficulties with thinking, problem solving or language
Genetic mutations in what proteins are thought to be implicated in early onset familial alzheimers disease (<65 years old)?
APP (Amyloid precursor protein)
Presenilins
Lipoprotein ApoE4
What are the main pathological features of alzheimers disease ?
Amyloid plaques (aggregates of Abeta fragment of the amyloid precursor protein APP)
Neurofibrillary tangles (aggregates of phosphorylated forms of the tau protein)
Neurodegeneration- hyper phosphorylated Tau and Abeta act synergistically to cause neurodegeneratio, loss of neurons in hippocampus and cerebral cortex
Loss of cholinergic neurons accounts for learning and memory deficit
Drugs currently available for treatment in alzheimer disease are not a cure but can be used to ________.
temporarily alleviate some symptoms or potentially slow disease progression
What category of drugs can be used to treat AD ?
Acetylcholinesterase (AChE inhibitors) reversible
Glutaminergic NMDA receptor antagonists
What AChE inhibitors can be used to treat mild to severe AD?
Donepezil
Galantamine
Rivastigmine
List some cholinergic side effects of AChE inhibitors
abdominal pain
diarrhoea
nausea
Dyspepsia
bradycardia
urinary incontinence
extrapyramidal symptoms- worsen parkinsons disease
Give an examples of a glutaminergic NMDA receptor antagonist used to treat moderate to severe AD
Memantine
When is the use of memantine indicated in treating AD?
for those unable to take AChE inhibitors
What class of drugs should be contraindicated with use of memantine ? Why ?
Other NMDA antagonists such as Amantadine (used to treat PD) and ketamine
This is because they increase CNS side effects
What are the side effects of memantine?
Balance disorders; constipation, dizzieness, drowsiness, dyspnoea (laboured breathing), headache, hypertension
Give some reasons why oral hygiene may be impaired in patients with AD?
Forget to or unable to remember how to brush teeth
Carers are often elderly spouses, need to cope with a lot, oral hygiene gets neglected
Dental considerations for patients with AD
schedule short appointments with care giver present
good communication
anxiety so avoid long/complex procedures
behaviour issues- include biting
memory loss- forgotten appointments, lost dentures
