cns w1
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Note: this lecture should mostly be a revision lecture
Types of channels
A change in voltage will lead to opening of the channel
Very fast response, very short duration
Voltage gated
A ligand binding to the channel directly opens it
Very fast response, very short duration
Ligand gated (ionotropic)
Ion channels
The G protein released from the ligand bound receptor will open a channel
Slow response, long duration
Direct
The G protein will activate an enzyme which produces secondary messengers which then
open a channel
Slow response, long duration
Indirect (secondary messengers)
Metabotropic
Sites of drug activity
Action potential is blocked from reaching the synaptic terminal
Ion channel blockers like anaesthetics do this
Conduction
Lecture 1- CNS and neurotransmitters
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Can increase or decrease synthesis of neurotransmitters
e.g. levodopa is used to increase the synthesis of dopamine
Synthesis
Stored neurotransmitters are depleted, so they won't be released as much leading to reduced
action
Reserpine causes this to monoamines (dopamine, noradrenaline and serotonin), may be used as
antipsychotic
Storage
More neurotransmitter released = more action (ignoring receptor tachyphylaxis)
Amphetamines causes increased release of monoamines (which is why people use P)
Release
Metabolism
Preventing degradation keeps more neurotransmitters in the cleft
Acetyl esterase breaks down ACh, which we can inhibit to treat Alzheimer's disease
Degradation
Keeps more neurotransmitters in the cleft (increases overall concentrations)
SSRIs (selective serotonin reuptake inhibitors) are an obvious example to treat depression
Reserpine (as seen above) causes depletion via inhibition of reuptake into the cell
Reuptake
Glial reuptake
Can antagonise or agonise the receptor to cause effects
Receptor binding
The post synaptic cell signals to the presynaptic cell to modulate effects
Anandamide (endogenous canabanoid) is an example, as it reduces the activity of the pre-synaptic
cell
Retrograde signalling
The presynaptic cell will detect neurotransmitter release and through negative feedback will
reduce activity
Autoreceptor
Receptors and neurotransmitters
The neurotransmitter causes the voltage within the neuron to increase
This moves the cell closer to the threshold voltage (may possibly excite the cell enough to trigger
an action potential)
Increases neuronal activity (excitatory)
Noradrenaline
Histamine
Glutamate
Acetylcholine
Examples:
Excitatory post synaptic potential
The neurotransmitter causes the voltage within the neuron to decrease
The moves the cell away from the threshold voltage (may possibly prevent an action potential
from being fired off)
Reduces neuronal activity (inhibitory)
Dopamine
Serotonin
GABA
Glycine
Examples:
Inhibitory post synaptic potential
Generally speaking, when a neurotransmitter binds to its receptor, it will have one of the following effects on
the neuron (not strictly true, but outside our scope):
Receptors Condition Synthesis and metabolism Pathways Drugs
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Serotonin '5-HT' series
5-HT3 is I
Rest are M
Depression Produced from tryptophan
Broken down by MAO
Raphe nuclei
Mood & sleep
SSRIs
Antiemetics
(ondansetron, 5HT3 ant.)
Clozapine 5HT2A ant.
Buspirone 5HT1A ag.
Sumatriptan 5HT1D ag.
NA Adrenoceptors
Alpha and beta
All are M
Depression
ADHD
Produced from dopamine
Broken down by MAO and
COMT
Locus coeruleus
Controls fear,
anger , mood
Noradrenaline reuptake
inhibitors (NRIs) for
depression
Methylphenidate blocksreuptake to treat ADHD
Dopamine D 1 to 6
D2 is an
inhibitory
autoreceptor
All M
Depression
Schizo
Parkinson's
Produced from DOPA (from
tyrosine)
Broken down by MAO and
COMT
Nigrostriatal (motor
control)
Mesolimbic/mesocorti
cal (emotion &
cognition)
Tuberoinfundibular
(prolactin release)
Dopamine precursors (L-
DOPA)
D2 antagonists (increases
dopamine)
ACh M1 to 4 and N
Muscarinic are M
Nicotinic is I
Parkinson's
Alzheimer's
Produced from choline and
acetyl-CoA
Broken down by ACh esterase
ACh esterase inhibitors
used for memory
(Alzheimer's)
Antagonists used as
antiemetics
Glutamate
Excitatory
AMPA (I), fast
NMDA (I), slow
Alzheimer's Amino acid
Can be synthesised from
glucose (Kreb's cycle) or from
glutamine in glia
Later lectures
GABA
Inhibitory
GABAA (I)
GABAB (M)
Epilepsy Produced from glutamate Later lectures
NA = noradrenaline
I = ionotropic
M= metabotropic (G protein)
Ant= antagonist
Ag= agonist
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Anxiety
Reflexes kick in
Sympathetic system activates
Become alert and ready
Cortisol secretion occurs (stress hormone)
Normally, it's a normal response to something which is dangerous (or just scary)
Especially when symptoms interfere with normal life
But the problem is in some people, this can occur without an external stimulus, or it's anticipatory, so it needs
to be treated
Fear related (panic attacks or phobias)
'General' anxiety, which tends to be genetic
There are two types of anxiety:
Social anxiety disorder (extreme shyness to the point where it's debilitating
Panic disorder (can be triggered by carbon dioxide)
Phobias, which there are a lot of different types
Panic attacks may be precipitated by certain triggers
Drugs to treat anxiety disorders
Anxi = anxiety
Lytic = remove/kill
Anxiolytic drugs are used to treat anxiety disorders
Quite handy, because it can treat insomnia as well
Wouldn't be surprised to see people with panic attacks having trouble sleeping
Remember: epilepsy is overexcitation of the neurones, so it makes sense that these drugs
would cause sedation due to its inhibitory effects
Originally developed for depression and epilepsy
Early drugs tended to cause sedation
This causes reduced neuronal activity, calms the person down.
Both work at the GABAA receptor, which causes an influx of chloride ions to cause
hyperpolarisation
Barbiturates aren't favoured anymore due to their addiction properties and it's easy to overdose
But benzodiazepines are good for certain kinds of anxiety disorders like post traumatic stressdisorder
Examples are benzodiazepines and barbiturates
Antidepressants for OCD and panic disorder (generally speaking, not the GABA agents above)
Propanolol beta blocker to prevent tremors and other symptoms
MAOIs (antidepressants)
Tricyclic antidepressants
Etc. (other antidepressants)
Remember: early drugs for anxiety were anticonvulsants
Anticonvulsants, such as gabapentin and valproate may also be used
Nowdays, we tend to use:
GABA
Most common inhibitory neurotransmitter in the brain
GABAA- opening will lead to an influx in chloride ions (inhibitory action)
Will bind to one of two receptors:
Lecture 2- Epilepsy and Anxiety (pharmacology)
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Anxiolytics work here
As well as hypnotic, anaesthetic and anticonvulsant (epilepsy) drugs
Ionotropic (fast onset and action)
Baclofen, used to treat muscle spasticity and alcoholism
Metabotropic (slow onset and action)
GABAB- associated with potassium channels (efflux of positive ions is an inhibitory action)
One for GABA, this is the 'normal' binding site, the others are all allosteric binding sites
Alcohol should not be taken with these medications, as they can work synergistically on the
GABA receptor
The other sites (benzodiazepines, barbiturates and alcohol) won't cause the pore to open, butinstead, they will allow GABA to bind more effectively to the channel
The GABAA receptor has several binding sites
Alpha (2x alpha 1)
Beta (2x beta 2)
Gamma (1x gamma 2)
In addition, there are many subtypes of the GABAA receptor, as they are made up of 5 different subunits
(the most common subtype is in brackets)
Benzodiazepine site is between beta and gamma
GABA sites are between alpha and beta units
The binding sites will sit between subunits
Alpha 1 is associated with sedation, 2 and 3 are associated with anxiolytic effects
Therefore, different subtypes of GABAA receptors can have different effects
The chloride ion pore is formed between the 5 subunits
Located both pre- and post-synaptically
Metabotropic receptors with Gi or Gq
Inhibits voltage gated calcium channels to reduce calcium influx to reduce neurotransmitter
release (remember, calcium causes vesicles to bind to the membrane to release their contents)
Also somehow causes opening of potassium channels, probably on the post synaptic membrane
to cause hyperpolarisation and to inhibit adenyl cyclase
The GABAB is different:
GABAA is faster and has a shorter period of action, because it's ionotropic, selective for chloride
channels
GABAB is slower and has a longer period of action, because it's metabotropic, does more than
just open a single channel, many mechanisms are involved
The difference between the two can be seen below
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Benzodiazepines
Work by binding to the allosteric site of the GABAA receptor
Causes increased inhibition in the CNS
Sedation
Amnesia (not always a bad thing, you'd want to forget dental procedures)
Confusion
Ataxia
Side effects are:
Problem is, they have a rebound effect if they are withdrawn, and will lead to loss of sleep and
will cause rebound anxiety as well
Triazolam is quite funny, because it causes this rebound in a few hours of dosing, and can make
elderly people quite cranky
Makes it hard to stop benzodiazepines, need to taper down
Receptor density can decrease
Tends to occur in epilepsy patients, because they are on benzodiazepines for long periods
of time at higher doses
Dependence and tolerance can occur as well with long term use
At lower doses, it will reduce anxiety, but at higher doses, it will induce hypnosis or sleep
Also used for status epilepticus (see workshop) to quickly try and reduce the seizures
Makes it suitable for 'cover therapy' for antidepressants
Although they are not effective in treating depression, since they work faster, it's a good idea to
give it to patients while waiting for the antidepressants to work
Rule of thumb, it will take 6-8 weeks for antidepressants to work, quite a long time, so this cover
therapy is important
These drugs work in 30 minutes
Ones with a long half-life are able to cause 'hangover effects'
Midazolam and zopiclone (both seem to be quite popular) have an 'ultrashort' duration of
action (4-6 hours)
Diazepam itself actually has a short half-life, but the problem is, its active metabolite,
nordiezapam, will accumulate as it's got a longer half-life. This leads to hangover symptoms
Therefore, one with a short half-life should be recommended to people who want to feel fresh in
the morning
Pharmacokinetics are important for benzodiazepines
Actually quite safe
No respiratory or cardiac depression (unlike opioids which can cause the former)Will only cause prolonged sleep
BUT if combined with alcohol, since they both work on the GABAA receptor, respiratory
depression can result
Overdose of benzodiazepines
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Epilepsy
High frequency of discharge, usually from a group of neurons called the 'focus'
Not all seizures will cause spasms (e.g. absence seizures, see workshop)
But if the motor cortex is being affected, then we can expect spasms
Passing out = complex seizure, not passing out = simple seizure
Similarly, since the reticular formation in the brain is involved in consciousness, if it's affected by a
seizure, then the person will lose consciousness
CNS disorder with periodic seizures
Classifications will not only include the 'complex' and 'simple' categories, but will also include if it's a
partial seizure (confined to one part of the brain) of if it's general (all over)
Genetic (common, 33%)
Brain injuries (including strokes, infections etc.) as well
The causes can be:
Drugs tend to be effective in about 70% of people, others may require surgery (e.g. electrode insertion)
It makes sense that these electrical signals will continue to be conducted across neurones
But in normal people, the brain's innate inhibitory responses will prevent the excitation from
travelling very far
But in people with seizures, the inhibitory response might not be good enough, or the excitatoryresponse might be facilitated by something
Remember how the NMDA and AMPA (both glutamate receptors) are involved in memory?
This mechanism is used to reduce the activity threshold required for neuronal firing.
This makes seizures more common and frequent as a result
To make things worse, it has elements from long term potentiation, where if certain neurones
were used often, then they will reach threshold much easier (leading to more seizures) 38.44
The mechanisms in seizures
[INCOMPLETE]
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Intro
Slow movement
Slow to initiate movement (delay before they start moving)
Plus they tend to fall over backwards very easily
Loss of postural reflexes, so they lean forward
Move around by leaning forward
Short quick shuffles
No arm swinging
Leads to Parkinsonsian gait
Bradykinesia (brady = slow, kinesia = movement)
'Pill rolling' tremor, rolling the thumb and index finder around in circles
Occurs at rest (may disappear when asked to move the arm)
Can get worse with emotional stress (if they're agitated, it gets worse)
Initially unilateral (i.e. only occurs in one arm), but can become bilateral (both arms) with
disease progression
Tremor
Stiff movement (cogwheeling). For example, they can't smoothly extend their arm, it's jerky
movement
Leads to pain, which is resistant to treatment with paracetamol. Need to treat the cause to
relieve this pain
Rigidity
Parkinson's disease has three major symptoms, which are all motor (movement) related
Postural hypotension
Impotence and bladder dysfunction
Autonomic dysfunction
Dementia and depression (worse with disease progression)
Hard to swallow, the swallowing reflex needs to be initiated with a voluntary movement
(which is difficult in these patients), and then it becomes involuntary reflex (which could
also become lost)
Dysphagia
Constipation
Writing in small font, due to stiffness
Micrography
And there are non-motor symptoms
Old age, starts around 40-70yr of age
Being Caucasian
Exposure to pesticides and heavy metals
Living in rural areas (maybe pesticides?)
High intake of fats
Occurs commonly between homozygous twins (strong suggestion that it's genetic, not
environmental)
Mutations in alpha-synuclein and parkin were identified
We need to remember the genetic environment interaction, because having a genetic
mutation will cause a massive increase in risk if they are exposed to an environmental risk
factor
Family history/genetics
Major stress
Head trauma
Prodrug which is converted into a toxic compound which specifically kills dopaminergic
MPTP
There are some risk factors for developing Parkinson's disease
Lecture 12 + WS6- Parkinson's Disease
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neurons in the brain, causing rapid onset of Parkinson's disease symptoms
Generally speaking, benefits seen from smoking are outweighed by the risks
And the evidence is from case-control studies (not the strongest form of evidence, as it
can't tell us much about causality, i.e. does X cause Y?)
Caffeine and cigarette smoking
Oxidative stress is implicated in the aetiology of the disease
Antioxidant intake
Early measles infection
Moderate beer consumption
And there are protective factors
This means it's important for voluntary movement
The pyramidal pathways of the brain extend from the motor cortex of the brain and they pass
through the pyramids of the medulla, down the spinal cord, and eventually directly innervate
motor neurones
Therefore, if it's affected, then control over muscle tone is lost, leading to stiffness
Plus it leads to movement disorders, like tremors
The extrapyramidal system also has neurones going down the spinal cord, but they are involved
in modulating voluntary movements (for example, co-ordination between muscles) and it's also
important for involuntary commands like muscle tone
Dopaminergic neurones are used
If they are killed off, then the system fails (as seen in Parkinson's disease)
The extrapyramidal system is regulated by the substantia nigra via the nigrostriatal pathway
To understand the pathophysiology, we need to look at some anatomy first
This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Authors: Selket
and Mikael Hggstrm. Retrieved from http://en.wikipedia.org/wiki/File:Spinal_cord_tracts_-_English.svg
60-80% of the neurones need to be killed before clinical symptoms are seen (could be used in the
future for screening, there must be a way to detect this massive loss of neurones)
Lumps of protein called Lewy bodies can be seen within the neurones
Can cause excitotoxicity
Free radical generation from the Fenton reaction (iron used to produce free radicals from
peroxide, a normal byproduct from oxidative metabolism)
Damage may have been due to oxidative damage
We're not sure why, but in Parkinson's disease, the dopaminergic neurones are killed off
Olfactory bulb, used for smelling
Autonomic system (see above for non-motor symptoms)
Serotoninergic and noradrenergic neurones are also killed off. These neurones are important for
mood, and they have been implicated in depression
Neurones are also killed off in:
Plus secondary Parkinson's disease is what happens if it's drug induced (i.e. the Parkinson's is caused by
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e.g. Haloperidol
Antipsychotics aim to reduce dopamine in the brain, as psychotic symptoms tend to be
associated with an excess in dopamine
Conversely, drugs used to treat Parkinson's disease (especially dopamine agonists) will
cause psychotic symptoms!
Antipsychotics
Blocking the dopamine receptor prevents signalling between the parts of the brain whichare involved in the vomiting reflex
Metoclopramide and prochlorperazine are dopamine receptor antagonists, so they can
cause Parkinson's like effects (especially resting tremors)
Therefore, it won't block dopamine in the brain
And remember, the chemosensor zone of the brain, used to initiate the vomiting
response is located outside the BBB
Domperidone is a dopamine antagonist which can be used for Parkinson's disease patients,
because it can't cross the BBB
Antiemetics
something other than neuronal destruction)
The dopamine hypothesis includes the fact that a reduction in dopamine leads to an imbalancewith ACh
Normally, the dopamine (inhibitory) inhibits ACh (excitatory) from causing any effects
But once the dopamine neurones die off, the ACh release can occur (disinhibition)
This causes the motor effects seen in Parkinson's disease
The pathology of Parkinson's disease is hypothesised to be due to a reduction in dopamine (especially
in the substantia nigra)
There are no biological or radiological markers, so you can't have a blood test and diagnose
Parkinson's disease from that
Need to go off the tremor, rigidity and bradykinesia
Plus they can have the other non-motor symptoms (see above)
There is no way to directly diagnose Parkinson's disease, other than to look at the symptoms
Problems relating to treatment
Random changes in responses to medication (dose independent)
Patients can fluctuate between the 'On' and 'Off' states several times a day
More likely to have dyskinesia
But they will have good mobility and response to medication
Therefore, patients might not mind the dyskinesia because they're able to move around
In the on state
The patient is more likely to experience bradykinesia
They will respond poorly to their medications
Increase in non-motor features, like mood swings
In the off state
Switch from controlled/sustained release (CR) to immediate release (IR) towards the end of
the day, because the accumulation due to CR use can cause dyskinesia
Add a COMT inhibitor, MAOI or dopamine agonist to allow for a reduced dose of levodopa
The on-off phenomenon is linked to high doses of levodopa (especially the dyskinesia), so the
only known way to mitigate the problem is to reduce the levodopa dose
On-off phenomenon
Reductions in motor function just before their next dose (dose dependent)
This is because the concentration of levodopa is too low, this will occur just before their doses
(see below)
See belowCan be solved using extended release products to keep plasma levels high
Wearing off
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But the problem is, they take longer to absorb (lag time), so it's a good idea to start the day with
fast acting IR product, then switch to CR product during the day to prevent wearing off
Notice how the plasma level drops below the minimum plasma level required for activity? This can be
improved through the use of CR products, because they keep the plasma level higher for longer, so the
period of time spent below the effective concentration is reduced.
Note: controlled release products are good for night time exacerbations as well (especially for night
time urinary incontinence), because they will keep plasma concentrations up overnight without having
to get up to take immediate release products.
Another way to prevent wearing off is to coadminister a COMT or MAO inhibitor to increase plasma
levels of levodopa
And finally, taking levodopa on an empty stomach reduces competition for absorption, this increases
the amount of levodopa reaching the brain (see below)
Treatments
Plus dopamine agonists won't cause worse psychotic effects in older people
Levodopa is favoured for older patients, because they aren't as likely to live long enough to
experience dyskinesia associated with long term levodopa use
Dopamine agonists, although isn't as good as levodopa, is favoured for younger patients,
otherwise they'll have to live for a long with levodopa associated dyskinesia
Firstline treatment is either a dopamine agonist or levodopa
Then they'd consider adding other drugs in later stages of the disease
And finally, apomorphine and surgery (deep brain stimulation) are the last treatments we have for the
worst cases
Dopamine precursor
Unlike dopamine, it can cross the blood brain barrier (BBB).
Levodopa
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Once it's in the brain, it will be metabolised into dopamine, to increase the amount of dopamine in the
brain to counter the loss
Good response rate (75%)
Takes up to 6 months for it to work (range 1-6 months)
Not so good for tremor, as it's associated with increased cholinergic activity
Works best for bradykinesia and ridigity
Most of the dose is metabolised by dopa decarboxylase in the gut wall (some in the tissues as
well)
Some of the dose is metabolised by COMT (tissues) and MAO (gut wall)
Only 1% of the levodopa dose reaches the brain
Levodopa is quite extensively metabolised
Tends to be carbidopa
A carbidopa + levodopa combination product is available (Sinemet)
Because the levodopa is metabolised less, more gets through to the brain
Because of the extensive metabolism by dopa decarboxylase, levodopa is usually given with a dopa
decarboxylase inhibitor
Therefore, taking the dose with food needs to be considered
They tend to still have quite a bit of dopamine neurones, and the dose of levodopa could betoo much.
Therefore, taking it with food can reduce side effects
Early stage patients are advised to take it with food
They could need more levodopa (especially to combat the wearing off effect)
Taking it on an empty stomach prevents competition with proteins for absorption, leading
to more levodopa reaching the brain
Last state patients are advised to take it on an empty stomach
Levodopa competes with amino acids (from dietary proteins) for absorption
Less reaches the brain = less effects
Pyridoxine (vitamin B6) increases the peripheral breakdown of levodopa
MAOIs can be used as monotherapy for very mild cases of Parkinson's disease
They CAN be combined (MAOI and levodopa), but a dose reduction in levodopa is required
(sourced from NZF), but do not use concomitantly for people with postural hypotension,
frequent falls, confusion and dementia.
Concomitant MAO inhibitor use can lead to hypertensive crisis
Contraindicated for use for patients with closed angle glaucoma (can increase intraocular
pressure)
Remember: these two classes of drugs work in opposite ways
Levodopa is trying to trigger dopamine receptor activation
Antipsychotics are trying to prevent dopamine receptor activation
Psychotic symptoms are a side effect of levodopa use due to dopamine receptoractivation
Clozapine low dose can be used in Parkinson's disease patients though
Antipsychotics cause a pharmacodynamic interaction
It interacts with certain medications:
Hallucinations
Delusions
Mania
Paranoia
Vivid dreams or nightmares
Psychotic symptoms
Nausea and vomiting (remember: dopamine is a part of the vomiting reflex)
Hypotension (especially postural hypotension, which makes them even more likely to fall over)
Common side effects are :
Frequent doses self-administered by the patient is the best solution
Because patients know when their off periods will be coming on, and they'll time their dose to
maximise their on period
The frequency of dosing with levodopa is also important
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Not as effective as levodopa
Plus it's likely to cause even worse psychotic symptoms and nausea
However, they are less likely to cause dyskinesia associated with levodopa
Not surprising to see it causes heart valve fibrosis and pulmonary fibrosis
Increased risk of myocardial infarction
Bromocriptine is one of these agents
Some are derived from ergot (fungus), and it's actually a toxin
Side effects include nausea, sleep attacks (narcolepsy like), oedema, hallucinations and postural
hypotension
Impulsive gambling and other risky behaviours
Has a very interesting side effect:
Ropinirole is a non-ergot dopamine agonist
If a person is stuck (unable to move) a sub cut injection of apomorphine will get them moving
again
Recommended for people with long and frequent off periods
MUST administer with domperidone (dopamine antagonist, doesn't cross the BBB), as it is
strongly ematogenic (will make the person vomit)
If they require lots of doses, then an apomorphine infusion is recommended
Need to tell the patient to move injection sites around frequently
Need to show the patient how to injection
Can pay a hospital aseptic dispensing unit to prepare syringes instead
Need to show how to open a vial and know how much to draw into the syringes
Broken vials have a 24 hour expiry (so make up a day's worth of syringes every morning)
Need to tell their family about this as well (especially if they are being cared for)
Patient information:
Has a rare side effect: haemolytic anaemia. Full blood counts need to be monitored
Apomorphine is used as a last-line drug, and as a rescue therapy
Dopamine agonists
Rasagiline is more potent, but it isn't funded
Selegiline is funded in NZ at the moment
So inhibiting it will increase dopamine levels
MAO is in the brain to break down dopamine into metabolites
So the levodopa concentrations will increase with concomitant MAOI use
But be careful in using them together, need to drop levodopa dose
But MAO is also involved in breaking down levodopa in the periphery and in the brain
Can be used as monotherapy for mild cases
MAO-B inhibitors
Normally, COMT doesn't break levodopa down by much. But if dopa decarboxylase is blocked bycarbidopa, then the COMT breakdown pathway becomes more important
Especially good for managing the 'wearing off' effect
So we can also give the person a COMT inhibitor to keep the levodopa going to the brain
Entacapone is available for use in NZ for this purpose
COMT inhibitors
Special class of its own
However, this isn't as good as levodopa though, with tolerance possible
Causes dopamine release and prevents it from being reabsorbed
NMDA receptor antagonist (somehow has an effect)
Anticholinergic effect (effective against tremor and rigidity)
But instead, it also has activity at:
Dopamine related:
Side effects are:
Amantadine
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Psychotic symptoms
Hypotension
Dry mouth
Constipation
Blurred vision
Anticholinergic effects:
Used as a late stage drug
Used as an adjunct to therapy, because they are not effective against bradykinesia, but they are good
for rigidity and tremor
Anticholinergics