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

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

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

ACh

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

Alzheimer's

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

GABA Inhibitory

GABAA (I) GABAB (M)

Epilepsy

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) It does the above by opening potassium channels to hyperpolarise the membrane to prevent any of the above actions from happening 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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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 exposed to kainic acid, even after the kainic acid was stopped So excitation toxicity may be involved in seizures for humans 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
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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 brain 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 of GABA, 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 phenobarbital 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)?
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 What happens with overdose (common)? 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 Also potentiates GABA receptors 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 It is also metabolised by CYP3A4, so it induces its own metabolism (autoinduction) Dose increases may be nessesary 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 + WS4- Medchem of anticonvulsants

Recap: mechanism of action (because the pharmacology lecture is a mess)
Works at/by First Generation Phenobarbital (barbiturates) Second gen Benzodiazepines GABAA Phenytoin Carbamazepine Na+ channels Increases response of GABA binding via binding to an allosteric site Stabilises inactive states of sodium channels (which are normally inhibited by GABAB activity) Primarily a sodium channel blocker (stabilises the inactive state, as above). Might also potentiate responses at GABA receptors Inhibits GABA reuptake Inhibits GABA transanimase to reduce breakdown, activates glutamamic acid decarboxylase to increase production Inhibits GABA transanimase Sodium channel blocker as well GABAA (ionotropic, Cl-) Increases response of GABA binding via binding to an allosteric site MOA

Na+ channels GABAB (metabotropic, Na+) Increases GABA Increases GABA

Tigabine Valproate Third gen Vigabatrin Lamotrigine

Increases GABA Na+ channels

Gabapentin

Ca2+ channels

Inhibits the channels to prevent pacemaker activity important for absence seizures

Barbiturates (first generation) The SAR of barbiturates is quite easy to understand and memorise:

Electronegative atom down the bottom Note: primidone does not have anything down there, it is a prodrug which is metabolised to form phenobarbital May be used as an anticonvulsant, but now being used for essential tremour At least 1 H on either of the nitrogens to binding to GABAA on the allosteric barbiturate binding site Both R groups at the top must be present, and that's due to lactam-lactim tautomerism, something which contributes to the pKa and activity of this drug If one of those groups was a hydrogen, a keto-enol tautomerism is possible as an H would be next to a keto group:

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 Notice how acidic the enol is (pKa of 4) This is a huge problem, because at pH 7, you'd expect this acid to be 99.9% ionised The ionised form cannot enter the brain. So the compound is inactive But if both R groups are not hydrogen, then we can see lactam-lactim tautomerism, which produces a lactim with a pKa of 7-8

This means it's only half of the molecules are ionised Therefore, significant amounts are able to enter into the brain to have an effect It is also important to note that the conjugate bases can be made into salts They are much more soluble, and they are able to be formulated as an injection They are basic (weak acid + strong base), so they are incompatible with acidic solutions They cannot be left standing in air They are basic solutions and they will absorb carbon dioxide from the air The carbon dioxide will enter into solution and produce carbonic acid The acid produced will neutralise the conjugate base, causing it to form the free acid once more The acid has a lower solubility, so it crashes out and precipitates, rendering the solution uninjectable The duration and onset of action depends on the lipophilicity of the molecule Lipophilic drugs are able to cross easier into the brain, so they have a faster onset of action, but a shorter duration Log P of about 2 is the best (100 times more concentrated in octanol than water) The barbiturate nucleus (the parts required for SAR pretty much ) has a log ) of -1.35 (hydrophilic) So the side chains mainly determine the lipophilicity of the molecule More branches and carbon atoms = more lipophilic Using S instead of O in the ring = more liphophilic To make something longer lasting, make it hydrophilic instead Barbiturates are metabolised in the liver Strong inducers of microsomal systems, i.e. CYPs as well (used to break down bilirubin) Be wary of CYP induction The R side chains can be oxidised during metabolism Or the ring can be hydrolysed Lastly, the side chains are also important in determining activity Phenyl (aromatic) group is required for activity against generalised seizures Alkyl groups (normal chains) allow it to work against absence seizures as well, but will also cause sedation

Second generation:
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Second generation: Phenytoin

Second generation anticonvulsant which looks similar to the barbiturates (notice the imides) However, binds to sodium channels, not the GABAA receptor It has a pKa of 8.4 as well (lactam-lactim) Not completely ionised, so it's able to enter the brain Notice it has phenyl groups, it can be used for generalised seizures Carbamazepine

Also works at the sodium channels Similar efficacy compared to phenytoin But less toxic Structure looks similar to TCAs (look at the rings) Valproate Doesn't work at the sodium channels (surprise!) Increases the production of GABA Activates glutamic acid decarboxylase (increase production) and inhibits GABA transanimase (decrease breakdown) May cause liver damage Third generation Drugs in this class have something to do with GABA (increase production or decrease breakdown); or inhibits glutamate on NMDA (part of seizure activity) See table above Benzodiazepines

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 The basic benzos will have 3 rings as above Things to consider: The electronegative group in the C ring will increase potency, but at the cost of excessive sedation effects Some benzos have a long sidechain at R1 in the B ring, if they are slowly demethylated, then it has a very long half-life Some of the second generation benzos will have a heterocyclic ring above the B ring:

As stated above, a carbonyl group next to the nitrogen in ring B gives the best activity But the problem is, it's susceptible to hydrolysis Since these second generation benzos don't have the carbonyl group, they won't be hydrolysed there We also need to consider the basicity of the benzos for salt formation They need to have a nitrogen which is sufficiently basic:

So all of these benzos may be made as an acidic salt (strong acid + weak base) for injection Of course, not all benzos contain a sufficiently basic nitrogen:

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 Triazolam (pictured above) has no basic enough groups The triazo ring is neutral The nitrogen at the bottom of the B ring is not basic enough (pKa of about 3, see above) Diazepam has the same problem, no basic enough nitrogen:

And finally, we need to consider their metabolism:

Diazepam itself doesn't have a very long half-life However, it produces a lot of active metabolites which have a longer half-life compared to diazepam, so they can accumulate to quite high levels It will only become inactivated once glucuridated (+glu in red on the diagram) So if a shorter half-life benzo is desired, consider the drugs along the metabolism pathway Temazepam is the benzo of choice for elderly patients (but they should be avoided) Why isn't diazepam metabolised by aromatic hydroxlylation? Uses a mechanism we haven't learned (and we don't need to know), but the electron withdrawing groups on the rings protects them Z drugs

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 Looks similar to the benzos, but they bind somewhere else to the GABAA receptor Very good drug because it doesn't have a long half-life, so there's no grogginess in the morning

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Lecture 4- Pharmacokinetics
NOTE: I couldn't go to this lecture, may be missing stuff Intro Pharmacokinetics is quite important for antiepileptic drugs (AEDs): Large variability in PK for these drugs, especially phenytoin If this is coupled with a low therapeutic index (narrow therapeutic range, TR), then there's a massive potential for overdose or underdose Therapeutic drug monitoring (TDM) is where we monitor the concentrations of a drug in a person to see if their dose is right Especially good for these types of drugs due to their PK and narrow TR Plus their response is hard to quantify without looking at the drug concentrations i.e. you can't tell if a person's anti epileptics are working just by looking at the person, unless they happen to be seizing, which in that case, means the medicine isn't working. And lastly, there's no point to doing TDM unless there's a correlation between PK and PD i.e. we need to know if changing a drug's concentration will be meaningful for the drug's effects Luckily, the AEDs show a dose-response correlation Problem is, the free concentration is the most important concentration. If the % bound changes at different concentrations, then the dose-response curve isn't linear. When to carry out TDM Levels should be taken at the trough level, i.e. just before they are about to take their next dose If not, then we need to note the time they took their last dose, so we can extrapolate to see if everything is alright Protip: if you say age is a significant risk factor for an adverse drug reaction, you'll be right. Therefore, TDM is especially important for these at-risk population groups You would want to do it for someone who is just starting their drugs, or are making changes to their dose Need to wait for steady state first, no point in taking a level too early, or you would underestimate their levels A level should be taken immediately if they are showing signs of toxicity A level should be taken if they are seizing, they might be being underdosed Check during pregnancy, the volume of distribution and the fraction bound are changing It could also be taken to see if they are fully compliant with the medication (a low level indicates they're slacking off) There are three drugs which we need to know the PK of. Carbamazepine (CBZ), phenytoin and phenobarbitone Carbamazepine Why are we studying CBZ? It's because of autoinduction Autoinduction In other words, it induces its own metabolism, so its clearance is increased as time goes by (2-3 weeks) It is metabolised by CYP3A4, and it induces CYP3A4 Main form of metabolism is to an epoxide, which is also active But the epoxide is able to be metabolised further into an inactive product To compensate for the autoinduction effects, the dosing regimen of CBZ is as follows: Start on a dose which is 25-30% of the normal maintanence dose. Because there's no induction of CYP yet, this small dose will be sufficient to get plasma levels into the therapeutic range (Blue line on diagram below)
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therapeutic range (Blue line on diagram below) Then increase the dose every week to compensate for the autoinduction, until in week 3, they should be receiving the full maintenance dose while being in the therapeutic range If a person was started off on the full maintenance dose, then you'd expect them to have a massive overdose in the first few weeks (red line). This is not ideal:

Not very soluble in aqueous solutions, absorption is slow and erratic Slow because the concentration gradient set up within the stationary layer is small due to the low solubility Erratic due to the various polymorphic crystalline forms CBZ is produced in Physical pharmacy just doesn't unlearn itself y'know :P Not only does it induce CYP3A4 (and a bunch of others), it also inhibits CYP2C19, which just happens to be the enzyme (+) warfarin uses. i.e. can increase INR, be careful It induces and inhibits a whole bunch of enzymes by the way Lastly, the therapeutic range for CBZ is quite lax i.e. Need to individualise therapy, need to get adequate control of seizures (increase dose if seizure, check plasma levels too just in case), while avoiding toxicity (decrease dose, check plasma level as well) Different people will need different levels Especially if they are taking different drugs which can induce or inhibit CYP enzymes Also, there is a problem with TDM with CBZ TDM doesn't measure the concentrations of the active metabolite, some people could have reduced glucuridation mechanisms, so they accumulate more of the active, which can lead to toxic effects TDM only measures the total concentration, no indication of free concentrations, as it can be anywhere between 75-90% bound to alpha-1-acid glycoprotein. Higher fraction unbound =more effects Phenytoin Why are we studying phenytoin? Because it shows capacity limited metabolism over the therapeutic range Protip: before reading the graphs in this section, you need to understand some are rate vs. concentration curves. DO NOT get them mixed up with concentration vs. time curves we normally see a lot of. Recap: For first order (and above) reactions, the concentration of the reactants (i.e. the drug) influences the rate of reaction. But for zero order reactions, the concentration of the reactants has no bearing on the reaction rate. Capacity limited metabolism Normally, you'd expect the rate of metabolism of a certain drug to be proportional to the concentration (i.e. first rate order), because if there's more drug around, then more of it would be removed:

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 But, with capacity limited metabolism, there's too much drug for the metabolising enzymes at higher concentrations. Adding more drugs can't increase the rate or metabolism because the enzymes are already fully saturated (zero order):

This relationship is shown through the Michaelis-Menton (M-M) formula:

Where: The dC/dt is the rate of metabolism Vmax is the maximal rate (see graph above) Determined by the amount of liver enzymes present Metabolised by CYP2C9 (major) and CYP2C19 (minor) This is a problem, lots of polymorphisms around 2C9, so dosing will be difficult Cp is the plasma concentration KM is the concentration of drug where half of Vmax is achieved More potent drugs will require a smaller concentrations to achieve Vmax So it's inversely proportional to affinity The M-M formula can explain what is going on: At low concentrations, We assume the plasma concentration is minimal, so it can effectively be ignored:

Since Cp is still in the formula, it shows that at low concentrations (when Cp is small compared to Km), the rate of reaction is still influenced by the plasma concentration (i.e. first order) But at high concentrations, Cp becomes a significant factor, so significant that Km is small compared to concentration, so Km can be ignored instead:

Since the two Cp will cancel each other out (by division), the rate is equal to Vmax only. Therefore, concentration has no bearing on rate of reaction (i.e. becomes zero order):

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 Why does this all matter? Because this is what it looks like if the plasma concentration is plotted against the dose rate:

This means a tiny change in dosing rate causes a huge change in concentration, enough to cause an under or overdose:

Therefore, if you're making adjustments, MAKE SMALL ADJUSTMENTS No more than 30mg a day Use a nomogram to estimate and adjust doses Make a calculation based on PK Just to make things a bit more complicated, we also have to take protein binding into consideration for phenytoin It binds to albumin instead (CBZ binds to alpha-1 globulin) Normally highly bound, 90% binding But with hypoalbumenia (occurring in HEPATIC FAILURE), several things happen: Since there's less albumin, there's less drug binding. Therefore, binding reduces to 80% BUT since now there's more free drug, more drug is able to be metabolised (bound drug can't be metabolised. This reduces the TOTAL concentration The decreased binding and increased metabolism offset each other, leading to the amount of FREE drug:

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 What does this all mean? If we carry out TDM on them, then their TOTAL levels appear low. But in reality, their FREE concentration hasn't changed, and the FREE concentration is within the therapeutic range, while the TOTAL concentration appears to be too low. Because of this, a prescriber may try to increase dose, which would result in a massive increase in drug levels due to capacity limited metabolism, so a massive overdose is possible So make sure you measure free concentrations in these people. NOT the total concentrations It induces enzymes such as CYP3A4 and UGT (i.e. be wary of interactions) And since it's metabolised by CYP2C19 and 2C9, it also inhibits them Warfarin again Different forms are available Phenytoin and phenytoin sodium They are not equivalent. Be careful when changing between them (100mg phenytoin sodium is equivalent to 92mg of free phenytoin) Plus be careful when changing between brands, quite different release profiles Finally, infusions can only be carried out at 50mg/min, due to its low solubility, pushing it too fast will cause it to precipitate out Normally kept soluble by PEG, which becomes diluted once infused Lastly, since overdoses can easily occur, we (and the patients) need to be aware of the signs and symptoms Nystagmus (twitchy eye movements) and blurred vision Ataxia (twitchy movements) Mental changes (slurred speech and sedation) Coma (obviously want to pick up on the other symptoms BEFORE arriving here) Misc drugs Valproate Poor correlation between plasma concentrations and efficacy, so taking levels might not mean much The reason for this is TDM doesn't take its many active metabolites into consideration Valproate is also protein bound (90%), so free levels need to be taken instead of total levels Funny thing is, it's metabolised by two things UGT which is induced by the two drugs we've just learned (CBZ and phenytoin induces UGT) And it's metabolised by beta oxidation in the mitochondria, because it's a fatty acid Minor pathway with CYP2C9 and 2C19 Lamotrigine Boring

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Lecture 5- Antipsychotics
Intro These drugs are mainly used to treat schizophrenia But may be used for bipolar disorder, depression and dementia For schizophrenia, we need to be aware there are two types of symptoms: Positive symptoms are symptoms which are additive to a normal person's behaviour: Delusions/paranoia Hallucinations (may be visual, auditory, smell etc.) Agitation and aggressive behaviour Negative symptoms are symptoms which are taken away from a normal person's behaviour: Loss of motivation Loss of emotions or empathy Reduced cognitive function Average reduction in 1 standard deviation in IQ, so the average drops from 100 to about 80 Social withdrawal Can't feel pleasure from the things which would normally bring pleasure These symptoms should have a minimum duration of 6 months

Dopamine According to the dopamine hypothesis, psychotic symptoms may originate from having high levels of dopamine in the brain Drugs which were agonists for dopamine made things worse, while antagonists made it better But with newer research, other receptors like serotonin, acetylcholine and NMDA (glutamate) are thought to be involved as well Chemically speaking, dopamine is a catecholamine, as it's a precursor to adrenaline and noradrenaline (which are the other two monoamines) There are 5 dopamine receptors, which are located postsynaptically: D1 like-excitatory by stimulating adenylate cyclase (increase cAMP) through a Gs (i.e. G protein) system D1 and D5 D2 like-inhibitory (causes hyperpolarisation) by inhibiting adenylate cyclase (decrease cAMP) through a Gi system. This opens K+ channels D2, D3 and D4 The majority of the actions are liked to D2 receptors There are four dopaminergic pathways we should consider to know about their effects and side effects Mesolimbic- blockade in D2 receptors will cause a reduction in positive symptoms, it's thought overactivity here leads to psychotic symptoms VTA to nucleus accumbens Mesocortical- blockade makes negative symptoms worse, it's normally responsible for mood, planning and other behaviour, so blocking that makes the negative symptoms worse VTA to cortex Nigrostriatial- normally used for motor control, blockade causes Parkinson's like effects Substentia nigra to striatum Tuberoinfundibular- goes to the pituitary from the hypothalamus. Dopamine normally inhibits the production of prolactin in the anterior pituitary. But if blocked, the inhibition is lifted, so prolactin production occurs, making people lactate Quick points: Before proceeding any further, you need to understand the D2 receptor is really important 80% binding needs to be achieved for the drug to work (quite high)
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 80% binding needs to be achieved for the drug to work (quite high) Binding affinity to the D2 receptor determines the potency of a drug (see below) The MOA for all types of these agents is probably through change in receptor numbers and affinity Receptors are upregulated after long periods of blockade, which is why these agents require at least 3 weeks to be effective Note: QT prolongation is common to all antipsychotics. Be wary when giving them to people with heart failure Typical antipsychotics (first generation)

Antagonists at D1, D2 and D4 (as long as it blocks D2, it's all good) Good for positive symptoms Remember: blocking D2 at the mesolimbic pathway reduces positive symptoms ...but can make negative symptoms worse, and it can't treat negative symptoms Remember: blocking D2 at the mesocortical pathways makes negative symptoms worse And since we know the nigostratial pathways are involved in motor control, blockade of these D2 receptors here by these antipsychotics causes extrapyramidal side effects (EPS) Dystonia- movement of eyes to one direction for minutes to hours. Usually looks upwards Torticollis- movement of the head or neck to one side, may be permanently kept there or spasmodic movement Akathisia- urge to move around (restless leg syndrome) May be treated with propanolol or cyproheptadine, an antihistamine Parkinson's like symptoms- rigidity, rolling pill tremors at rest and bradykinesia (can't move) Treat with anticholinergics, can't use dopaminergics as they'd cause positive symptoms Plus adding a dopamine agonist can make it WORSE Be wary of anticholinergic effects (dry mouth, constipation, burred vision) Tardive dyskinesia- uncontrolled movements of limbs and tongue Permanent, irreversible Thought to be due to induction of dopamine receptors in the striatum over a long period of treatment Occurs less with atypical antipsychotics Risk is higher in the elderly The potency can affect the side effect profile: Low potency- increases in anticholinergic effects and constipation, but is less likely to produce EPS Chlorpromazine etc. High potency- decreases antichonilergic effects and constipation, but more likely to produce EPS Haloperidol or prochlorperazine etc. Good for quick action where someone needs to be treated ASAP Depot injections have a higher risk of EPS Note: because there are these trade offs involved, consulting the patients to see what side effects they'd prefer is a good idea And blockage of the tuberoinfundibular pathway causes lactation, also decrease in libido and gynecomastia (man boobs) and amenorrhoea (menstrual cycles stop) and possibly galactorrhoea (inappropriate lactation) Causes changes in metabolic effects Weight gain Hyperlipidemia Hyperglycemia All associated with heart disease
Atypical antipsychotics (second generation) These agents are considered to be first line agents for new cases of schizophrenia and psychoses Plus patients with side effects or relapses with typical agents should change to a atypical agent

Clozapine

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 Only causes a weak D2 blockade, instead it hits and blocks other receptors Especially the 5-HT2A receptors (serotonin) But others include muscarinic, adergenic, and histamine receptors If the brain is mapped, then we can see the D2 receptors have only been slightly upregulated in the VTA, while the 5-HT receptors are massively upregulated in the cortex Because it only has a small effect on dopamine receptors in the VTA, EPS are reduced But it causes nausea, sedation, tachycardia and seizures It's effect on serotonin receptors allows it to be effective against negative symptoms Compared to the typicals which make negative symptoms worse It's selective for the cortical receptors as well (remember: mesocortical pathway is involved in negative symptoms) Good for cases of refractory and resistant cases. Because of it's side effects (esp. agranulocytosis), it is used as a third line agent Need to use at least one other atypical agent before switching to clozapine Warning: may cause agranulocytosis, careful monitoring of blood counts is required Abnormal blood counts are a contraindication to starting therapy Monitor blood counts weekly for the first 18 weeks, then monthly after that If bloods come back abnormal, stop immediately and refer to haematologist Other drugs which can cause agranulocytosis should be avoided Patients need to know about the symptoms, especially the flu-like ones The others (listed briefly), non subsidised meds not listed Aripriprazole As expected (weak D2 and strong 5-HT2A antagonist) but also stimulates 5-HT1A Olanzapine As expected plus H1 antagonism Associated with massive weight gains and stronger side effects But is the most efficacious Quetiapine Weak binding to both receptors Not good as an antipsychotic, use for depression and anxiety instead Risperidone As expected but also binds to alpha 1 and 2 adrenoreceptors Good for negative symptoms No EPS or agranulocytosis, making it more attractive Problem is the prolactin related side effects are more likely and severe As for side effects, weight gain (and associated heart disease) is a huge worry for this class EPS isn't much of a worry here due to weaker D2 antagonism

Guidelines
It is thought that having a strong D2 antagonist for the positive symptoms and some 5-HT2A antagonism is good for negative symptoms. BUT in most patients, polypharmacy with these agents isn't recommended. Remember: they all have QT elongation as a side effect Only to be used if clozapine by itself isn't working Doses should be started low and titrated upwards Halved in old patients Good patient education is important, they need to be aware it can take up to 3 weeks for the drugs to start working (remember: that upregulation in receptors is important for pharmacological effect) Depot formulations only need to be administered every 2 or 4 weeks Very good for people with compliance issues Monitoring ECG is probably a good idea, especially with elderly patients who are at risk Metabolic monitoring is also a very good idea
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 Metabolic monitoring is also a very good idea Weight and BMI monthly Fasting glucose (what about HbA1c?) at least annually, monthly or quarterly for at-risk patients Lipids at least annually, quarterly for people starting on atypicals Non-compliance is a huge issue with these drugs, given their side effects Education is important They can talk to their doctor about changing agents if they don't like the side effects

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Lecture 6- Antidepressants
Depression Affective disorder Hard to distinguish from other natural processes like grieving, so we use the DSM-V guidelines to make a diagnosis Note: it's the same as DSM-IV, but grief due to bereavement can be diagnosed within a few weeks instead of 2 months The important things are low mood + a loss in pleasure from things which would normally bring pleasure. These two symptoms must be sustained for at least 2 weeks along with three others: Behavioural Changes in weight (loss or gain) Changes in sleeping patterns (insomnia or hypersomnia) Changes in movement (slowed or sped up) Fatigue Cognitive Feeling worthless or guilty Can't think straight or concentrate Suicidal thoughts Pathophysiology The amine hypothesis is behind our current way of thinking about depression There are three monoamine neurotransmitters Serotonin Noradrenaline Dopamine And we think depression is caused by a lack of these transmitters, so the aim of therapy is to increase their concentrations in the brain Drugs which decreased monoamines caused depression, and vice versa But the theory isn't perfect, depression might be fixed by targeting other neurotransmitters However, since it takes 6-8 weeks for the drugs to start working, there must be sometime else going on The receptor hypersensitivity hypothesis assumes the number and sensitivity of these receptors is just too high, which is why it's causing depression Using these drugs for 6-8 weeks causes the post synaptic membrane to downregulate and desensitize receptors in response to the increase in monoamine concentrations The downregulation and desensitization causes receptor function to drop down to normal levels Plus we have to take the brain into consideration: The hypothalamus-pituitary-adrenal axis (HPA axis) overactivity is linked to depression (seen as smaller hypothalamus volumes) Increased secretion of corticotropin releasing hormone from the hypothalamus to the pituitary This causes an increase in adreno-corticotropin releasing hormone (ACTH) to the adrenal cortex This causes an increase in cortisol production from the adrenal glands This stimulates glucocorticoid receptors in the hypothalamus, which causes reduced hypothalamus volume Cortisol therefore causes depression as it leads to deregulation in neurotransmitters Neurotropic factor hypothesis Brain derived neurotrophic factor (BDNF) is a protective protein found in the brain It's thought that low levels are linked to depression, as a lack of it can cause cell death, especially if the death occurs in the hippocampus Also important for plasticity of neurones (the ability to make new connections) as that function is important for mood The production of BDNF is triggered by long term use of these drugs
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 The production of BDNF is triggered by long term use of these drugs 33% of people who try an antidepressant will be non-responders Even after 8 weeks, the antidepressant won't work Need to replace it with something which does work Drugs, drugs, drugs

Monoamine oxidase inhibitors (MAOIs) Reversible inhibitors of monoamine oxidase A (RIMAs) Tricyclic antidepressants (TCAs) Selective serotonin reuptake inhibitors (SSRIs) Serotonin and noradrenaline reuptake inhibitors (SNRIs) Noradrenaline reuptake inhibitors (NARI) Reboxetine only, NOT subsidised Increases action of serotonin

MAOIs Monoamine oxidase (MAO) normally breaks down noradrenaline and serotonin, so it increases their levels in the brain by preventing them from breaking down Reminder: we want to increase the levels of these monoamines Phenelzine and Tranylcypromine are in this class, and they inhibit both forms of MAO in the synaptic cleft to increase the concentration of the monoamines in the cleft Suicide inhibitors, because they are metabolised in the active site, but doing so, it causes the inhibitor to be irreversibly bound to the enzyme This inhibition is so strong and it takes so long to remake the enzymes, a 2 week washout period is required Rather difficult to use drugs as they bind irreversibly and unselectively to both MAO-A and B enzymes This causes the Cheese effect. Cheese (and yeast products like Marmite, even soy sauce) are rich in tyramine, a compound with adergenic effects, but it's broken down by MAO. Since MAO is blocked, it causes massive hypertension and death This also means they can't use other adergenics like oxymetazoline used for nasal congestion MUST NOT be used for the same reason A throbbing headache is the most common early symptoms of hypertensive attack Side effects: Postural hypotension (care: falls risk) Anticholinergic effects (dry mouth, blurred vision, constipation) (also a falls risk) Weight gain, restlessness and insomnia due to CNS stimulation REMA Pretty much the same as MAOIs Less likely to cause hypertensive crisis, but should still stay well away from excessive consumption Moclobemide works within the presynaptic terminal (not in the cleft) to increase the amount of monoamines within the terminal Causes more to be released Although hypertensive crisis is less likely, it's also less efficacious But, since it's reversible, stopping the treatment will stop the side effects, unlike the above, which are irreversible Otherwise, side effect profile is the same as MAOIs TCAs They block the uptake of serotonin and noradrenaline, so they are technically SNRIs Competes for the ATPase section of the enzyme, if it can't use ATP, it can't pump Doesn't matter if they have a stronger action against one or the other, blocking either is still efficacious Since their reuptake is inhibited, there's more serotonin and NA, so they have more effect
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Since their reuptake is inhibited, there's more serotonin and NA, so they have more effect But in addition, they also have effects elsewhere: Alpha adrenoreceptor antagonists Muscarinic M1 antagonist Anticholinergic effects are strong Be very careful if using it for elderly patients (in fact, not recommended) Histamine H1 antagonist As above Can reduce the threshold for seizure activity, may precipitate seizures Can cause weight gain, use with care in overweight patients Big problem is they also block L-type calcium channels. You know, the ones which generate heart beats. Overdoses tend to be fatal for this reason Charcoal and diazepam stat to absorb as much of it as possible, while the diazepam stops seizures Bicarbonate to counter metabolic acidosis Also, to be used with caution for people with heart conditions In fact, contraindicated for use for people with arrhythmias Examples of drugs in this class include amitryptyline, nortriptyline, doxepin and imipramine Amitryptyline is really potent, so it has a high efficacy, but also most likely to have severe side effects While Nortriptyline is the least potent, so it's recommended for elderly patients (not they should be recommended TCAs as first line anyway) And these drugs aren't just used as antidepressants Anitryptyline may be used as a sedative TCAs work against neuropathic pain somehow They also have annoying PK Highly protein bound, be wary in liver failure or other conditions Has active metabolites with long half-lives. This means there's little relationship between the dose of the parent drug and the effects Dose accordingly (start low, go slow)

SSRIs First choice Not dangerous in overdose compared to TCAs Since these people afterall, are the type of people who would really like to swallow a bunch of pills. We need to be careful. The pharmacology isn't very simple: Firstly, inhibits the reuptake transporter to increase levels of serotonin in the cleft If the increase is sustained for long enough, the 5-HT1A, 1B/1D receptors on the presynaptic membrane get downregulated This is important, because these receptors are autoinhibitory receptors, i.e. if serotonin binds to these receptors, then the synapse will release less serotonin So if downregulation occurs of these receptors, in the long run, the amount of serotonin in the cleft will increase as the autoinhibitory response becomes blunted Since now there are two mechanisms which causes increases in serotonin, it causes the 5-HT2 receptors to downregulate as well Remember: the downregulation of this receptor is important, as the receptor sensitivity hypothesis suggests these receptors are overexpressed in depression [INSERT DIAGRAM] But they are still associated with some side effects Nausea and vomiting as expected Stimulation of serotonin in the chemoreceptor trigger zone (CTZ) in the hypothalamus Diarrhoea and cramping due to local GI activation of serotonin receptors Sexual dysfunction is a problem Most obviously, serotonin syndrome will occur if another drug is increasing serotonin, like
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 Most obviously, serotonin syndrome will occur if another drug is increasing serotonin, like tramadol, MAOIs or even lithium. Check for interactions Restlessness, tremours, sweating, confusion, convulsions and death Evidence for supportive fluids only Fun fact: St John wort can cause serotonin syndrome as well Serotonin receptor activation in basal ganglia of the brain Causes EPS (see previous lecture) Although it's an antidepressant, it might cause an increase in suicidal thoughts. CONTRAINDICATED if a patient reports suicidal thoughts (a drug company got their pants sued off because of this) Can cause hyponatremia In fact, is common to all antidepressants Monitor sodium for the first 2 weeks when starting and changing doses Refer if below normal Can increase bleeding risk with NSAIDs Can cause agitation and anxiety attacks due to serotonin as well Fluoxetine (one of the most popular ones) has an active metabolite, nor-fluoxetine. Therefore, it has a very long half-life, be wary of accumulation and drug-drug interactions SNRIs Pretty much an intermediate between a SSRI and TCA Action pretty much the same Serotonin is affected more at lower doses (as stated above though, it doesn't matter) Also hits muscarinic receptors, so expect anticholinergic side effects Examples are venlafaxine and duloxetine High dose Venlafaxine has a short onset of action for fast results, but may lead to hypertension Duloxetine is the most potent Venlafaxine is a third line drug, consider SSRIs first They have active metabolites with long half-lives. Be wary Too many antidepressants, doesn't look important, skipping. Not worth it Mirtazapine Noradrenaline and specific sertotonin antidepressant (NaSSA) Blocks presynaptic adrenoreceptors (so it will cause desensitisation and increase the release of noradrenaline as the autoinhibitory response is blunted, see above) Blocks postsynpatic serotonin HT2 and HT3 receptors, good for preventing suicidal idelation Most potent of them all Surprisingly low side effect profile Reserved for patients who have tried and failed at least 2 antidepressants Washouts and switching antidepressants Really big list Should look it up instead Generally, 2-4 days for most things Fluoxetine has a long half-life, need 1 week Non-selective MAOIs need a 2 week Switching from anything to nonselective MAOIs need a week Except fluoxetine again, needs 5 weeks Misc Pregnancy and children? We don't know Use TCAs, they have the most evidence, seems to be relatively safe
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 Use TCAs, they have the most evidence, seems to be relatively safe Antidepressants MUST be taken for at least 6 months to prevent relapse, as it can occur if stopped too early Bipolar Characterised by episodes of depression (sad) and mania (opposite of sad) Two types Bipolar I Full on mania Usually requires hospitalisation due to delusions or hallucinations Elevated mood is the most common symptom Marked impairment of normal function (e.g. go on an extreme spending spree, or remain awake for a few weeks) May or may not have depression Bipolar II Hypomania Elevated mood, but function isn't affected much Won't require hospitalisation Depression occurs Lithium is the best drug Works for both manic and depressive episodes But of course, it's nephrotoxic and requires a lot of TDM and has a lot of interactions Thyroid function Can cause hypothyroidism Check function before use, and monitor Sodium Lithium is treated very similarly as sodium by the body Anything which increases sodium secretion like loop or thiazides will increase clearance Dehydration Dangerous, because dehydration will increase the concentration of lithium This can precipitate renal failure Diarrhoea and vomiting can trigger dehydration, be aware Monitor Electrolytes Lithium Thyroid ACE and NSAIDs will prevent lithium excretion, expect increased levels Except aspirin Other drugs include lamotrigine, CBZ and valproate (these are AEDs, lecture 2)

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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 http://en.wikipedia.org/wiki/File:Spinal_cord_tracts_-_English.svg 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 Clinically proven to prolong the duration of disease free years 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)
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 NMDA receptor antagonist (somehow has an effect) 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, adjunct to other treatments 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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Lecture 8- Medchem of antiparkinsonian drugs

Intro Parkinson's disease is due to dopaminergic neurones not working in the nigrostriatal pathway Therefore, treatment focuses on increasing stimulation of dopamine receptors to allow movement The function of dopamine was to inhibit ACh The function of ACh is to inhibit movement Therefore, reduced dopamine reduces the inhibition on ACh, so there's more of it, which causes reduced movement

DOPA
Although the obvious choice seems to be giving a person more dopamine, the problem is, dopamine is a charged molecule, so it can't cross the BBB But, the precursor to dopamine, DOPA, can be taken up into the brain through active transport. Therefore, we use DOPA as a therapy to increase dopamine levels in the brain DOPA is decarboxylated to form dopamine in the brain

A problem with DOPA is the fact that decarboxylase enzymes also exist in the periphery as well, which causes two problems: Since it's metabolised before it gets to the brain, it reduces the amount of DOPA in the brain, reducing its effectiveness Since it's metabolised to dopamine, the dopamine produced will cause side effects, notably nausea and vomiting Therefore, we co-administer DOPA with a decarboxylase inhibitor Carbidopa- most commonly used. Either in 1 carbidopa :4 DOPA or 1:10 ratios Benserazide- also used, more potent compared to carbidopa, comes as a 1:4 ratio Both seem pretty similar to DOPA, due to their aromatic ring to the left, and nitrogen containing chain to the right

At therapeutic concentrations, these decarboxylase inhibitors can't cross the BBB, so they won't cause a decrease in efficacy at the brain, while reducing side effects in the periphery. Amantadine Originally an antiviral compound High pKa of 10, but it's basic, so it won't be ionised The cage like structure of carbon at the bottom gives it lipophilicity, to allow it to cross the BBB
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 The cage like structure of carbon at the bottom gives it lipophilicity, to allow it to cross the BBB It also prevents oxidation reactions, remember: oxidation reactions tend to make the molecule more hydrophillic

Dopamine agonists These substances will be direct agonists of the dopamine receptors Unlike dopamine, they are able to cross the brain Comes in two general classes Egrot based, more side effects and chance of fibrosis of the heart valves. Not as selective, hits D1 and D2 receptors Non-egrot based. Hits D2 receptors specifically Ropinerole is a non-egrot compound:

May be formulated as a salt, as the nitrogen to the left is basic enough (pKa 9.5) HCl salt Bromocriptine, an egrotamine, is more complicated, which is expected as it's a derived from a natural source

May also be formulated as a salt, one of the nitrogens is basic enough Mesylate salt The structure of bromocriptine is relatively rigid, as it has several rings in the structure Also notice the huge number of stereocentres in this molecule (I can count at least 5) So natural synthesis of the precursor is important to get these stereocenters right Apomorphine is a derivative of morphine The nitrogen is basic (pKa of 9), so it's expected to be ionised But, it's lipophilic enough to cross the blood brain barrier due to the lots of carbon

Selegiline- MAO-B inhibitor

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Selegiline- MAO-B inhibitor MAO-B deanimates dopamine, so blocking it is a good idea Selegiline can block MAO-B Plus it acts as a dopamine reuptake inhibitor to further increase dopamine levels It contains a stereocenter, the S form is the eutomer (the one with more effects), while the R form is the distomer It contains one basic nitrogen in the middle (I'm going to guess a pKa of 9-10ish) Formulated as a HCl salt

Has been shown to increase the symptom free period during Parkinsons disease Can be used in mild cases on its own or as an adjunct to treatment Mechanism is due to the prevention in the formation of a MPP+ like toxin Turns out MAO-B aids the production of these toxins by being in the pathway involved in its production Therefore, blocking MAO-B slow the progression of the disease Interestingly, it's a fully subsidised, but section 29 med COMT inhibitors MAO-B is one enzyme which breaks down dopamine, the other is COMT Good idea to block COMT while blocking MAO-B, because if MAO-B is blocked, more is metabolised by COMT Tolcapone has a long half-life (10h) and it acts in the brain and peripheries, which should make it a good drug, but It is implicated in fulminant (sudden) hepatic failure, so it's not used Entacapone has a shorter half-life (2h) and only acts in the peripheries But at least it won't destroy livers quite as easily

Anticholinergics Remember: one reason why the symptoms occur is due to the brain now having too much ACh, so reducing ACh will help Reduced tremours due to ACh activation But has no effect on the rigidity, that's caused by a lack of dopamine Problem is of course, they have anticholinergic side effects Anticholinergics have a basic SAR:

Note: if this structure is to be compared with the one below, it needs to be flipped around R1 and R2 are usually heterocyclic rings
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 R1 and R2 are usually heterocyclic rings Not in the case of atropine R3 may be an H, OH, CH2OH (as in atropine) The X linker can be an ester or ether, but isn't required The optimum distance between the N and the ring is 2 carbons (i.e. n=2) But in reality, it has a bicyclic structure:

Notice how the relatively rigid structure keeps the positively charged nitrogen away from the heterocyclic ring, this distance is important Also notice how it also has a stereocentre (red circle) Atropine is just the name that's given to a racemate of Hyoscyamine, as the L-hyoscyamine is the eutomer, but it racemises in-vitro anyway Example of a drug: procyclidine Notice it fulfils all of the SAR requirements above

Antiemetic- domperidone Dopamine receptor stimulation in the chemoreceptor trigger zone (CTZ) will cause nausea and vomiting Luckily, its outside the BBB, so blocking it won't cause reduced efficacy in the brain Domperidone is a dopamine receptor antagonist to prevent the nausea and vomiting For some reason I don't know, it doesn't cross into the BBB, so it only blocks the receptors in the CTZ I'm going to guess the nitrogen in the middle is ionised due to it's relatively high pKa Use is recommended with dopamine agonists Use is REQUIRED with apomorphine

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Lecture 9- Medchem of antipsychotics and antidepressants

Intro Antipsychotic medications focus on reducing the activity of dopamine (and serotonin) in the brain Phenothiazine antipsychotics They all have the same common 3 ring structure They are typical antipsychotics (selectivity for antagonism at D receptors, no or little activity at serotonin receptors) Two broad things can modify the potency of this class: The substituent at the 2nd carbon (X below) Needs to be electron withdrawing Therefore, halogens at this position produces potent compounds due to their high electronegativity The side chain on the 10 nitrogen Should be 3 carbons long for optimal activity Having a tertiary amine covering the 2 substituent Note: the 10 nitrogen may be charged at physiological pH, but overall, since the molecule contains two aromatic carbon rings, it's lipophilic enough to get past the BBB

The phenothiazine class can further be subdivided based on the side chain Aliphatic amines are the most potent with higher sedative and anticholinergic effects Pictured below is chlopromazine, the most potent typical antipsychotic. Notice how it has a Cl electron withdrawing group (just flip the molecule around) The sidechain has 3 carbons It also has a tertiary amine (in reality, it should be pointing towards the chlorine, not away like the diagram below)

Piperidines are relatively similar to the above compounds (thioridazine, none available in NZ) Piperizines are the least potent with higher extrapyramidal effects Prochlorperazine is pictured below 20 times less potent compared to chlopromazine Although the nitrogen is a tertiary nitrogen, it's bulky, giving it less potency

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Thioxanthenes Similar to the phenothiazines, as thioxanthenes are bioisosteres as the 10 nitrogen has been replaced with a similar functional group:

Exactly the same rules apply from the phenothiazines (where R is the side now) But with one twist, since there is a double bond, we can now have cis-trans isomerism (technically E-Z isomerism, but whatever.) If the side chain is cis (Z) with the substituent (i.e. is going towards the substituent) it's much more potent Again, the reason for this is similar to that for phenothiazines, if the tertiary amine is close to the X substituent, its more potent The only one which exists in NZ is flupentixol, as you can see from the structure, it will have low potency (Z isomer shown below)

Butyrophenones
More potent compared to phenothiazines Less sedative and anticholinergic effects, but more likely to develop extrapyramidal symptoms Haloperidol belongs to this group There are a few features which are required for SAR: Fluorine in the 4 position (red) Ketone group (green) 4 carbons between the aromatic ring and the piperidine ring (blue) Basic nitrogen (orange) Note: it's lipophilic enough to cross the BBB

Quick note: atypicals

They are able to bind to the 5-HT2A receptor (serotonin) in addition to the dopamine receptor This is for the treatment of negative symptoms
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 This is for the treatment of negative symptoms Also gives axiolytic properties (i.e. may be used as a antidepressant) Their potency at the D2 receptor is reduced compared to the typicals, so they are less likely to produce extrapyramidal side effects Depot formulations

People who are psychotic tend not to be compliant with their medications Therefore, giving an IM injection is a good idea as it only needs to be given once every 2 weeks or so Problem is, it's associated with an increase in extrapyramidal side effects The major modifications seen on depot injections is of course a very long chain e.g. haloperidol can come in a decanoate form (decanoate in blue):

The ester will be cleaved slowly, releasing the active, free form of the drug over time Then we have other methods of forming a depot, as the above depends on cleaving an ester. While the next one changes the physical properties of the drug itself:

This is Olanzapine (blue) pamoate (orange) It is an insoluble salt, so once injected, it will release the drug slowly over time More soluble in the plasma at least, so it can be taken up properly into the body

TCAs
Looks quite similar to the typical antipsychotics, and that's because they have a three ring structure, with two benzene rings surrounding a central ring But the difference is the central ring for TCAs has 7 atoms, not 6 like the typicals The central ring may be a heterocycle, incorporating nitrogen or oxygen atoms Other things required for SAR are: 3 carbon side chain The side chain has a terminal amine (i.e. an amine at the end) which can either be secondary or tertiary The tertiary amines cause more anticholinergic and antihistamine effects (sedation) e.g. amitriptyline has a tertiary amine, while nortriptyline has a secondary amine. Therefore, amitriptyline has more anticholinergic and sedating effects, so it's not recommended for use in the elderly
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recommended for use in the elderly

In addition, the tertiary amines are more likely to inhibit serotonin uptake, while secondary amines are more likely to affect noradrenaline uptake Because of the difference between the 6 membered ring in seen in typicals and the 7 membered ring in TCAs, they have different geometry: The 6 membered ring will lead to a relatively flat and straight molecule While the 7 membered ring introduces significant torsion, so the molecule appears to be bent and twisted They are all metabolised by CYP2D6 (be wary of interactions) And CYP2D6 SSRIs No SAR found Yay MAOIs They appear similar to the molecule on the left, which can either be dopamine or noradrenaline (noradrenaline has OH for the R group, dopamine has H) Note: will also do the same to serotonin, but not shown below MAO will deanimate the molecule via oxidation (structure on the right)

Moclobemide(a reversible inhibitor) is somewhat similar, with a ring to the left and nitrogens and stuff

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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 of lithium 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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