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Lecture 1- CNS and neurotransmitters

Note: this lecture should mostly be a revision lecture Types of channels Ion channels Voltage gated A change in voltage will lead to opening of the channel Very fast response, very short duration Ligand gated (ionotropic) A ligand binding to the channel directly opens it Very fast response, very short duration Metabotropic Direct The G protein released from the ligand bound receptor will open a channel Slow response, long duration Indirect (secondary messengers) The G protein will activate an enzyme which produces secondary messengers which then open a channel Slow response, long duration

Sites of drug activity

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Conduction Action potential is blocked from reaching the synaptic terminal Ion channel blockers like anaesthetics do this Synthesis Can increase or decrease synthesis of neurotransmitters e.g. levodopa is used to increase the synthesis of dopamine Storage 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 Release More neurotransmitter released = more action (ignoring receptor tachyphylaxis) Amphetamines causes increased release of monoamines (which is why people use P) Metabolism Degradation Preventing degradation keeps more neurotransmitters in the cleft Acetyl esterase breaks down ACh, which we can inhibit to treat Alzheimer's disease Reuptake 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 Glial reuptake Receptor binding Can antagonise or agonise the receptor to cause effects Retrograde signalling 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 Autoreceptor The presynaptic cell will detect neurotransmitter release and through negative feedback will reduce activity Receptors and neurotransmitters 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): Excitatory post synaptic potential 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) Examples: Noradrenaline Histamine Glutamate Acetylcholine Inhibitory 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) Examples: Dopamine Serotonin GABA
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GABA Glycine
Receptors Serotonin '5-HT' series 5-HT3 is I Rest are M Condition Depression Synthesis and metabolism Produced from tryptophan Broken down by MAO Pathways Raphe nuclei Mood & sleep Drugs SSRIs Antiemetics (ondansetron, 5HT3 ant.) Clozapine 5HT2A ant. Buspirone 5HT1A ag. Sumatriptan 5HT1D ag. Noradrenaline reuptake inhibitors (NRIs) for depression Methylphenidate blocks reuptake to treat ADHD


Adrenoceptors Alpha and beta All are M

Depression ADHD

Produced from dopamine Broken down by MAO and COMT

Locus coeruleus Controls fear, anger , mood

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 Dopamine precursors (Lcontrol) DOPA) Mesolimbic/mesocorti D2 antagonists (increases cal (emotion & dopamine) cognition) Tuberoinfundibular (prolactin release) ACh esterase inhibitors used for memory (Alzheimer's) Antagonists used as antiemetics Later lectures


M1 to 4 and N Parkinson's Muscarinic are M Alzheimer's Nicotinic is I

Produced from choline and acetyl-CoA Broken down by ACh esterase

Glutamate AMPA (I), fast NMDA (I), slow Excitatory


Amino acid Can be synthesised from glucose (Kreb's cycle) or from glutamine in glia Produced from glutamate

GABA Inhibitory



Later lectures

NA = noradrenaline I = ionotropic M= metabotropic (G protein) Ant= antagonist Ag= agonist

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Lecture 2- Epilepsy and Anxiety (pharmacology)

Anxiety Normally, it's a normal response to something which is dangerous (or just scary) Reflexes kick in Sympathetic system activates Become alert and ready Cortisol secretion occurs (stress hormone) But the problem is in some people, this can occur without an external stimulus, or it's anticipatory, so it needs to be treated Especially when symptoms interfere with normal life

There are two types of anxiety: Fear related (panic attacks or phobias) 'General' anxiety, which tends to be genetic
Panic attacks may be precipitated by certain triggers 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 Drugs to treat anxiety disorders Anxiolytic drugs are used to treat anxiety disorders Anxi = anxiety Lytic = remove/kill Early drugs tended to cause sedation Quite handy, because it can treat insomnia as well Wouldn't be surprised to see people with panic attacks having trouble sleeping Originally developed for depression and epilepsy Remember: epilepsy is overexcitation of the neurones, so it makes sense that these drugs would cause sedation due to its inhibitory effects Examples are benzodiazepines and barbiturates Both work at the GABAA receptor, which causes an influx of chloride ions to cause hyperpolarisation This causes reduced neuronal activity, calms the person down. 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 stress disorder Nowdays, we tend to use: 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) Anticonvulsants, such as gabapentin and valproate may also be used Remember: early drugs for anxiety were anticonvulsants GABA Most common inhibitory neurotransmitter in the brain Will bind to one of two receptors: GABAA- opening will lead to an influx in chloride ions (inhibitory action)
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GABAA- opening will lead to an influx in chloride ions (inhibitory action) Anxiolytics work here As well as hypnotic, anaesthetic and anticonvulsant (epilepsy) drugs Ionotropic (fast onset and action) GABAB- associated with potassium channels (efflux of positive ions is an inhibitory action) Baclofen, used to treat muscle spasticity and alcoholism Metabotropic (slow onset and action) The GABAA receptor has several binding sites One for GABA, this is the 'normal' binding site, the others are all allosteric binding sites The other sites (benzodiazepines, barbiturates and alcohol) won't cause the pore to open, but instead, they will allow GABA to bind more effectively to the channel Alcohol should not be taken with these medications, as they can work synergistically on the GABA receptor

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) Alpha (2x alpha 1) Beta (2x beta 2) Gamma (1x gamma 2) The chloride ion pore is formed between the 5 subunits The binding sites will sit between subunits Benzodiazepine site is between beta and gamma GABA sites are between alpha and beta units Therefore, different subtypes of GABAA receptors can have different effects Alpha 1 is associated with sedation, 2 and 3 are associated with anxiolytic effects The GABAB is different: 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 difference between the two can be seen below 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

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open a single channel, many mechanisms are involved

Benzodiazepines Work by binding to the allosteric site of the GABAA receptor Causes increased inhibition in the CNS Side effects are: Sedation Amnesia (not always a bad thing, you'd want to forget dental procedures) Confusion Ataxia At lower doses, it will reduce anxiety, but at higher doses, it will induce hypnosis or sleep 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 Dependence and tolerance can occur as well with long term use Receptor density can decrease Tends to occur in epilepsy patients, because they are on benzodiazepines for long periods of time at higher doses Also used for status epilepticus (see workshop) to quickly try and reduce the seizures These drugs work in 30 minutes 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 Pharmacokinetics are important for benzodiazepines Ones with a long half-life are able to cause 'hangover effects' Therefore, one with a short half-life should be recommended to people who want to feel fresh in the morning 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 Overdose of 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 Epilepsy
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Epilepsy CNS disorder with periodic seizures 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 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 Passing out = complex seizure, not passing out = simple seizure 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) The causes can be: Genetic (common, 33%) Brain injuries (including strokes, infections etc.) as well Drugs tend to be effective in about 70% of people, others may require surgery (e.g. electrode insertion) The mechanisms in seizures 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 excitatory response might be facilitated by something Long term potentiation and seizures 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) 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 Possible changes in: Number of receptors Amount of neurotransmitters released How cells respond to t he receptors This makes seizures more common and frequent as a result The theory is called the kindling theory 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) If AMPA antagonists are given, then this potentiation response doesn't occur THIS IS WHY we give antiepileptics prophylactically after head trauma to prevent seizures by preventing kindling Another model to consider is the kainate model 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 Lastly, we also have to consider neurotrophins 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 For research purposes, seizures can be induced 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 Drugs which can block PTZ induced seizures AND electrical seizures are good for absence seizures Seizures can be induced by electrocuting parts of the brain (in lieu of an action potential)
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seizures Seizures can be induced by electrocuting parts of the brain (in lieu of an action potential) Drugs which can only block electrically induced seizures are good for focal seizures Paroxysmal depolarising shift and antiepileptics 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 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 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 Can work at: Sodium channels (want to block, because it's used to generate action potentials) 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. GABAA receptors (want to increase activity, because it's inhibitory) 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) Calcium channels (want to block, because it causes the initial depolarisation) 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 GABA transanimase(want to block to increase GABA levels) Vigabatrin and valproic acid will block GABA transanimase Valproic acid also activates glutamate acid decarboxylase, which produces GABA GABA reuptake (want to block to increase GABA levels in the synapse) Tiagabine prevents reuptake Glutamate release (want to prevent, because it activates NMDA)

Phenytoin Use dependent sodium channel blocker Used against generalised and partial seizures Not useful against absence seizures (remember: they need calcium channel blocking) Causes CYP3A4 induction Be wary of interactions Can be affected by phenobarbitone and alcohol, as they increase metabolic enzymes used to break down phenytoin (CYP2C9) Which is a pain, because CYP2C9 has polymorphisms as well Minor metabolism by CYP2C19 Polymorphs also exist Warning: saturable metabolism, leads to funky kinetics (see next lecture) Plus since polymorphs exist, it makes phenytoin a very hard drug to dose Age will reduce the rate of metabolism as well Again, see next lecture for full kinetics What happens with overdose (common)? Mild: vertigo, ataxia (poor motor coordination), headache and nystagmus (involuntary, twitchy
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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. Carbamazepine Use dependent block of sodium channels Effective on seizures except for absence seizures Also good for neuropathic pain (remember: anaesthetics tend to be use dependent channel blockers) and bipolar disorder Induces CYP3A4 Be wary of interactions Side effects are mild Sedation, ataxia, water retention etc. Valproate Effective on all types of seizures (including absence seizures) 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, and prevent pacemaker activity) Well tolerated as well Baldness Teratogenicity Rare liver damage Ethosuxemide Blocks T-type calcium channels (long acting, the ones with pacemaker activity) Good for absence seizure Can exacerbate other forms of epilepsy Also well tolerated Nausea Anorexia Levetiracetam 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

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Lecture 3- Medchem

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Lecture 4- Pharmacokinetics
Intro Pharmacokinetics is quite important in

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Lecture 7 + WS6- Parkinson's Disease

Intro Parkinson's disease has three major symptoms, which are all motor (movement) related Bradykinesia (brady = slow, kinesia = movement) Slow movement Slow to initiate movement (delay before they start moving) Loss of postural reflexes, so they lean forward Plus they tend to fall over backwards very easily Leads to Parkinsonsian gait Move around by leaning forward Wide gait for stability Short quick shuffles No arm swinging Tremor '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 Rigidity 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 And there are non-motor symptoms Autonomic dysfunction Postural hypotension Impotence and bladder dysfunction Dementia and depression (worse with disease progression) Dysphagia 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) Constipation Micrography Writing in small font, due to stiffness There are some risk factors for developing Parkinson's disease 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 Family history/genetics 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 Major stress Head trauma MPTP Prodrug which is converted into a toxic compound which specifically kills dopaminergic
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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 And there are protective factors Caffeine and cigarette smoking 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?) Antioxidant intake Oxidative stress is implicated in the aetiology of the disease Early measles infection Moderate beer consumption To understand the pathophysiology, we need to look at some anatomy first 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 This means it's important for voluntary movement 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 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 is regulated by the substantia nigra via the nigrostriatal pathway Dopaminergic neurones are used If they are killed off, then the system fails (as seen in Parkinson's disease)

This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Authors: Selket and Mikael Hggstrm. Retrieved from We're not sure why, but in Parkinson's disease, the dopaminergic neurones are killed off 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 Damage may have been due to oxidative damage Can cause excitotoxicity Free radical generation from the Fenton reaction (iron used to produce free radicals from peroxide, a normal byproduct from oxidative metabolism) Neurones are also killed off in: 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 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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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) Antipsychotics 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! Antiemetics 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) Domperidone is a dopamine antagonist which can be used for Parkinson's disease patients, because it can't cross the BBB 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 The pathology of Parkinson's disease is hypothesised to be due to a reduction in dopamine (especially in the substantia nigra) 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 There is no way to directly diagnose Parkinson's disease, other than to look at the symptoms 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) Problems relating to treatment On-off phenomenon Random changes in responses to medication (dose independent) Patients can fluctuate between the 'On' and 'Off' states several times a day In the on state 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 off state The patient is more likely to experience bradykinesia They will respond poorly to their medications Increase in non-motor features, like mood swings 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 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 Wearing off 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) Can be solved using extended release products to keep plasma levels high See below

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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. 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 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 Firstline treatment is either a dopamine agonist or levodopa 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 Plus dopamine agonists won't cause worse psychotic effects in older people 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 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 Adjunct therapies: Fluticortisone (mineralocorticoid) retains salt and water to treat postural hypotension Anticholinergics to relieve tremor

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Levodopa + carbidopa 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) Works best for bradykinesia and ridigity Not so good for tremor, as it's associated with increased cholinergic activity Levodopa is quite extensively metabolised 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 Because of the extensive metabolism by dopa decarboxylase, levodopa is usually given with a dopa decarboxylase inhibitor Tends to be carbidopa A carbidopa + levodopa combination product is available (Sinemet) Because the levodopa is metabolised less, more gets through to the brain Levodopa competes with amino acids (from dietary proteins) for absorption Therefore, taking the dose with food needs to be considered Early stage patients are advised to take it with food 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 Last state patients are advised to take it on an empty stomach 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 It interacts with certain medications: Pyridoxine (vitamin B6) increases the peripheral breakdown of levodopa Less reaches the brain = less effects Concomitant MAO inhibitor use can lead to hypertensive crisis 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. Contraindicated for use for patients with closed angle glaucoma (can increase intraocular pressure) Antipsychotics cause a pharmacodynamic interaction 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 Clozapine low dose can be used in Parkinson's disease patients though Psychotic symptoms are a side effect of levodopa use due to dopamine receptor activation Common side effects are : Psychotic symptoms Hallucinations Delusions Mania Paranoia Vivid dreams or nightmares 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) The frequency of dosing with levodopa is also important Frequent doses self-administered by the patient is the best solution
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The frequency of dosing with levodopa is also important 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 Dopamine agonists 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 Some are derived from ergot (fungus), and it's actually a toxin Not surprising to see it causes heart valve fibrosis and pulmonary fibrosis Increased risk of myocardial infarction Bromocriptine is one of these agents Ropinirole is a non-ergot dopamine agonist Side effects include nausea, sleep attacks (narcolepsy like), oedema, hallucinations and postural hypotension Has a very interesting side effect: Impulsive gambling and other risky behaviours Apomorphine is used as a last-line drug, and as a rescue therapy 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 Patient information: Need to tell the patient to move injection sites around frequently Need to show the patient how to injection Need to show how to open a vial and know how much to draw into the syringes Can pay a hospital aseptic dispensing unit to prepare syringes instead 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) Has a rare side effect: haemolytic anaemia. Full blood counts need to be monitored MAO-B inhibitors Selegiline is funded in NZ at the moment Rasagiline is more potent, but it isn't funded MAO is in the brain to break down dopamine into metabolites So inhibiting it will increase dopamine levels But MAO is also involved in breaking down levodopa in the periphery and in the brain So the levodopa concentrations will increase with concomitant MAOI use But be careful in using them together, need to drop levodopa dose Can be used as monotherapy for mild cases COMT 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 So we can also give the person a COMT inhibitor to keep the levodopa going to the brain Especially good for managing the 'wearing off' effect Entacapone is available for use in NZ for this purpose Amantadine Special class of its own Causes dopamine release and prevents it from being reabsorbed However, this isn't as good as levodopa though, with tolerance possible But instead, it also has activity at: NMDA receptor antagonist (somehow has an effect) Anticholinergic effect (effective against tremor and rigidity)
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Anticholinergic effect (effective against tremor and rigidity) Side effects are: Dopamine related: Psychotic symptoms Hypotension Anticholinergic effects: Dry mouth Constipation Blurred vision Used as a late stage drug

Anticholinergics 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 Obviously has anticholingergic side effects Dry mouth Blurred vision Constipation Urinary retention

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WS3- Pharmacokinetics
NOTE: I missed this workshop, apologies if this looks quite bare (feel free to contact me if you have anything to add) Paper summaries

Finlay Thiazide diuretics cause an increase in levels Monitor closely 40% dose reduction is recommended (or just use loop diuretics) Furosemide and other loop diuretics might reduce lithium clearance Significance isn't completely known Suggests monitoring if they need to be used together Osmotic diuretics (e.g. mannitol) increase clearance (can be used as an antidote) It's not likely anyone is going to need mannitol, as it's IV treatment for emergencies Amiloride (potassium sparing) is safe for use ACE inhibitors will increase lithium levels as well Monitor closely if started Verapamil (calcium channel blocker) might not cause any changes, but it still could cause an increase (monitor) SSRIs MIGHT interact as well Case studies show toxicity Also serotonin syndrome possible Halloperidol and other antipsychotics can be used with lithium, but again, there are case reports Cardiac events (QT elongation) Neurotoxicity The same holds true with TCAs as well
Raghab Aspirin (at analgesic doses) appears to have no significant effect on lithium levels 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 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 Roller Waste of time 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?
Suggestions Aspirin Because PGE production causes the pain, a NSAID is the best for dealing with the pain Aspirin doesn't interact with lithium Paracetamol General mild pain reliever Can be given with aspirin if required Non-pharmacological
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Non-pharmacological Hot water bottle

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?
Suggestions PRICER 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 Avoid HARM in the first 48 hours Heat Alcohol Running (or other activities) Massage Paracetamol for pain No NSAIDs, maybe except for aspirin 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? Suggestions 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 Non-pharmacological is again recommended Suck on ice 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. Suggestions A change is not recommended, Celecoxib will increase serum lithium levels But an advantage is it will reduce GI side effects 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) She would need to go on corticosteroids if other anti-inflammatory treatment is required Need to be careful with monitoring, because steroids can still have some mineralocorticoid activity, which can affect electrolytes and lithium 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 done before lithium treatment. What would you recommend as an antipyretic and why? Suggestions Aspirin is alright to take But paracetamol is recommended, because it's just as effective as ibuprofen as an antipyretic (while
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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) Suggestions: Diphenhydramine Least likely to affect lithium Corticosteroids Be wary of electrolyte disturbances Monitor lithium levels after use?

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