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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

Lecture 1- CNS and neurotransmitters

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Action potential is blocked from reaching the synaptic terminal

Ion channel blockers like anaesthetics do this

Conduction

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 reducedaction

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

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):

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GABA

Glycine

Receptors Condition Synthesis and metabolism Pathways Drugs

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 blocks

reuptake 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

The mechanisms in seizures

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.

i.e. a high frequency action potential sent into the presynaptic neuron will make the postsynaptic

neuron more prone to firing

Number of receptors

Amount of neurotransmitters released

How cells respond to t he receptors

This makes seizures more common and frequent as a result

Possible changes in:

Low level electrical stimulation in the brain causes no seizure

But after long term repetitive stimulation causes seizures

This 'kindled' state is permanent (like potentiation)

Removing the focus (the damaged area) might not treat the person, because a secondary

focus will then start to generate seizures instead (remember how excitation tends to

spread)

The theory is called the kindling theory

THIS IS WHY we give antiepileptics prophylactically after head trauma to prevent seizures

by preventing kindling

If AMPA antagonists are given, then this potentiation response doesn't occur

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)

Kainic acid is an excitatory compound, because it's a glutamate agonist

This leads to structural changes in neurones and neurotoxicity in inhibitory neurones

So seizures were seen in rats treated with kainic acid

Another model to consider is the kainate model

Brain derived neurotropic factor (BDNF) works with TrkB

We saw TrkB before, it's a tyrosine kinase receptor which is a part of the potentiation process

If TrkB is deleted, then kindling doesn't occur

Lastly, we also have to consider neurotrophins

Drugs which can block PTZ induced seizures AND electrical seizures are good for absence

seizures

Pentylenetetrazol (PTZ) can be used to increase the excitability of neruones (possibly a GABA

antagonist, so it makes the mouse brain like a person with epilepsy), which causes seizures

For research purposes, seizures can be induced

Long term potentiation and seizures

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Drugs which can only block electrically induced seizures are good for focal seizures

Seizures can be induced by electrocuting parts of the brain (in lieu of an action potential)

This activity appears to be similar to NMDA (glutamate) activation

Excessive activity will lead to excitotoxicity of the neurones (and neuronal death)

Problem is, blocking glutamate receptors doesn't prevent seizures, it appears to be a very

widespread receptor, so blocking NMDA receptors isn't a good idea

Paroxysmal Depolarising Shift (PDS) is where calcium mediates depolarisation, which leads to sodium

channels to open, causing action potentials to fire. Then the entire cell becomes hyperpolarised

(voltage drops past resting potential) for a short time afterwards

PDS will cause millions of nerves to fire, leading to a very flat curve on an EGG

So the purpose of antiepileptic drugs is to prevent PDS, while not affecting normal function

Use dependent block, where the drug stabilises the inactivated state of the receptor after

it's used

It shuts down the excited parts of the brain specifically, because it's use dependent.

Sodium channels (want to block, because it's used to generate action potentials)

Works by increasing the effect of GABA binding

Remember: the GABAA receptor has that co-binding site to increase action

e.g. bezodiazepines (midazolam), barbituates (phenobarbital) and z drugs (zopiclone)

GABAA receptors (want to increase activity, because it's inhibitory)

Involved in 'pacemaker' activity for generating absence seizures

So drugs which block calcium channel function will be effective against absence seizures

Gabapentin was designed to act like GABA, but instead, it works by blocking calcium

channels

Calcium channels (want to block, because it causes the initial depolarisation)

Vigabatrin and valproic acid will block GABA transanimase

Valproic acid also activates glutamate acid decarboxylase, which produces GABA

GABA transanimase(want to block to increase GABA levels)

Tiagabine prevents reuptakeGABA reuptake (want to block to increase GABA levels in the synapse)

Glutamate release (want to prevent, because it activates NMDA)

Can work at:

Paroxysmal depolarising shift and antiepileptics

Use dependent sodium channel blocker

Not useful against absence seizures (remember: they need calcium channel blocking)

Used against generalised and partial seizures

Be wary of interactions

Causes CYP3A4 induction

Which is a pain, because CYP2C9 has polymorphisms as well

Can be affected by phenobarbitone and alcohol, as they increase metabolic enzymes used to break

down phenytoin (CYP2C9)

Polymorphs also exist

Minor metabolism by CYP2C19

Plus since polymorphs exist, it makes phenytoin a very hard drug to dose

Age will reduce the rate of metabolism as well

Warning: saturable metabolism, leads to funky kinetics (see next lecture)

Again, see next lecture for full kinetics

What happens with overdose (common)?

Phenytoin

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Mild: vertigo, ataxia (poor motor coordination), headache and nystagmus (involuntary, twitchy

eye movement)

Will lead to confusion, gum hypertrophy, megaloblastic anaemia (due to folic acid dysfunction)

etc.

Effective on seizures except for absence seizures

Also good for neuropathic pain (remember: anaesthetics tend to be use dependent channelblockers) and bipolar disorder

Use dependent block of sodium channels

Be wary of interactions

Induces CYP3A4

Sedation, ataxia, water retention etc.

Side effects are mild

Carbamazepine

Inhibits GABA transanimase (prevent breakdown of GABA)

Activates glutamamic acid decarboxylase (synthesizes GABA)

Some effect on sodium and calcium channels (good to stop action potential production, andprevent pacemaker activity)

Effective on all types of seizures (including absence seizures)

Baldness

Teratogenicity

Rare liver damage

Well tolerated as well

Valproate

Good for absence seizure

Can exacerbate other forms of epilepsy

Blocks T-type calcium channels (long acting, the ones with pacemaker activity)

Nausea

Anorexia

Also well tolerated

Ethosuxemide

Used when phenytoin can't be used (e.g. due to enzyme induction)

Not effective for in-vivo tests (doesn't stop electrically induced or PTZ induced seizures)

Thought to prevent neurotransmitter release

Excreted unchanged in the urine

Levetiracetam

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Lecture 3- Medchem

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Intro

Pharmacokinetics is quite important in

Lecture 4- Pharmacokinetics

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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

Wide gait for stability

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

MPTP

There are some risk factors for developing Parkinson's disease

Lecture 7 + WS6- Parkinson's Disease

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Prodrug which is converted into a toxic compound which specifically kills dopaminergic

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:

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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 which

are 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

Plus secondary Parkinson's disease is what happens if it's drug induced (i.e. the Parkinson's is caused by

something other than neuronal destruction)

The dopamine hypothesis includes the fact that a reduction in dopamine leads to an imbalance

with 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 below

Can 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

Amantidine can be given late stage (see below)

And finally, apomorphine and surgery (deep brain stimulation) are the last treatments we have for the

worst cases

Fluticortisone (mineralocorticoid) retains salt and water to treat postural hypotension

Anticholinergics to relieve tremor

Adjunct therapies:

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Dopamine precursor

Unlike dopamine, it can cross the blood brain barrier (BBB).

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 activityWorks 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 be

too 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 receptor

activation

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 :

The frequency of dosing with levodopa is also important

Levodopa + carbidopa

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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

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 by

carbidopa, 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 possibleCauses dopamine release and prevents it from being reabsorbed

NMDA receptor antagonist (somehow has an effect)

But instead, it also has activity at:

Amantadine

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Anticholinergic effect (effective against tremor and rigidity)

Psychotic symptoms

Hypotension

Dopamine related:

Dry mouth

Constipation

Blurred vision

Anticholinergic effects:

Side effects are:

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

e.g. Benztropine, trihexylphenidate and procyclidine

Dry mouth

Blurred vision

Constipation

Urinary retention

Obviously has anticholingergic side effects

Anticholinergics

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NOTE: I missed this workshop, apologies if this looks quite bare (feel free to contact me if you have

anything to add)

Paper summaries

Monitor closely

40% dose reduction is recommended (or just use loop diuretics)

Thiazide diuretics cause an increase in levels

Significance isn't completely known

Suggests monitoring if they need to be used together

Furosemide and other loop diuretics might reduce lithium clearance

It's not likely anyone is going to need mannitol, as it's IV treatment for emergencies

Osmotic diuretics (e.g. mannitol) increase clearance (can be used as an antidote)

Amiloride (potassium sparing) is safe for use

Monitor closely if startedACE inhibitors will increase lithium levels as well

Verapamil (calcium channel blocker) might not cause any changes, but it still could cause an increase

(monitor)

Case studies show toxicity

Also serotonin syndrome possible

SSRIs MIGHT interact as well

Cardiac events (QT elongation)

Neurotoxicity

Halloperidol and other antipsychotics can be used with lithium, but again, there are case reports

The same holds true with TCAs as well

Finlay

But a few people might have a change

NZF says aspirin can be taken with lithium, and there is no interaction

For other NSAIDs, it recommends monitoring

Aspirin (at analgesic doses) appears to have no significant effect on lithium levels

Sulindac appears to have no clinically significant effect of lithium levels

Diclofenac, ibuprofen, naproxen and indomethacin all increased serum lithium levels

Lithium doses should be decreased if an NSAID except for aspirin is needed

Raghab

Waste of time

Roller

Case studies

Case Study One

A female patient, stabilised on lithium, wishes to take medication to relieve period pain. This would be only

for 1 to 2 days each month. What would you recommend?

Because PGE production causes the pain, a NSAID is the best for dealing with the pain

Aspirin doesn't interact with lithium

Aspirin

General mild pain reliever

Can be given with aspirin if required

Paracetamol

Suggestions

WS3- Pharmacokinetics

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Hot water bottle

Non-pharmacological

Case Study Two

A male patient, stabilised on lithium, has severely sprained his ankle. What can be recommended to reduce

inflammation and to control pain?

Prevent injury

Rest

Apply ice (20 minutes every 2 hours or so)

Compression (bands are good, take off before going to sleep)

Elevate ankle

Refer if not resolved in 48 hours

PRICER

Heat

Alcohol

Running (or other activities)

Massage

Avoid HARM in the first 48 hours

No NSAIDs, maybe except for aspirin

Paracetamol for pain

Suggestions

Case Study Three

A male patient, stabilised on lithium, has had a surgical extraction of a tooth. Severe pain and inflammation

has occurred. What would you recommend?

Paracetamol and codeine for pain

Aspirin if still painful (try and get rid of the inflammation)

Lignocaine gel for pain relief is possible as well

Suck on ice

Non-pharmacological is again recommended

Suggestions

Case Study Four

A female patient, who has bipolar disorder, is stabilised on lithium and regularly takes diclofenac (SR) for her

arthritis. She complains of mild GI side effects. What would be the advantages and disadvantages of changing

to celecoxib (instead of the diclofenac) for chronic treatment of her arthritis. Discuss the procedures that will

be necessary if her anti-inflammatory treatment is changed.

But an advantage is it will reduce GI side effectsA change is not recommended, Celecoxib will increase serum lithium levels

So it's a good idea to keep her on whatever she's already stable with

Therefore, add omeprazole to treat the GI side effect, and continue treatment (plus it's only mild GI

effects anyway)

Need to be careful with monitoring, because steroids can still have some mineralocorticoid

activity, which can affect electrolytes and lithium

She would need to go on corticosteroids if other anti-inflammatory treatment is required

Suggestions

Case Study Five

An elderly male patient, recently stabilised on lithium, is concerned about getting the flu and experiencing a

very high temperature. He asks whether it is still OK to take aspirin for the high temperature, as he has donebefore lithium treatment. What would you recommend as an antipyretic and why?

Aspirin is alright to take

Suggestions

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But paracetamol is recommended, because it's just as effective as ibuprofen as an antipyretic (while

being associated with less side effects, especially GI effects)

Case Study Six

A young female patient, recently stabilised on lithium for bipolar disorder, has just been stung very badly by a

wasp just before entering the Pharmacy. She is known to show a moderate allergic reaction to bee stings and

has some antihistamine tablets in reserve for such an emergency. Her last bee sting occurred before she

started taking lithium. Will administering oral antihistamines and/or prednisone for the wasp sting influence

her lithium dosage requirements?(Note: she NEEDS to take antihistamine or other medication to limit the allergic reaction to the wasp sting)

Least likely to affect lithium

Diphenhydramine

Be wary of electrolyte disturbances

Monitor lithium levels after use?

Corticosteroids

Suggestions: