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Pharmacology Year 2 > CNS Pharmacology > Flashcards

CNS Pharmacology Flashcards

1
Q

What do a) Sedatives b) Hypnotics c) Anxiolytics treat?

A

a) Anxiety

b) Sleep disorders

c) ANxiety

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2
Q

What are 5 effects of the Fear Response in animals?

A

1) Defensive behaviors
>Protects animal from danger

2) Autonomic reflexes
>Activation of ANS in mammals is associated with fear (fight or flight).

3) Alertness
>CNS goes into hightened response

4) Corticosteroid secretion
>Endocrine system mediates anxiety response
>Cortisol is a steroid excreted when fear response is activated

5) Negative emotions
>Fear responses give out negative emotions.

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3
Q

What is the definition of anxiety?

A

Anxiety – anticipatory fear response, which is often independent of external events

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4
Q

What is the difference between the Fear Response in humans and other animals?

A

In animals these fear responses are reactionary, humans have anticipatory fear responses

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5
Q

What are the 3 classes of anxiety and why is it important for pharmacologists to understand?

A

1) Panic disorder, Social anxiety , and Phobias

2) Post-traumatic stress disorder and Obsessive compulsive disorder

3) Generalized anxiety (no clear reason or focus)

> Different types of anti-anxiety medicines work different on different types of anxiety.

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6
Q

What was the first class of drug used as a anxiolytic?

A

Benzodiazepines

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7
Q

What are 3 animal models used to study anxiety and what is the expected reaction of the animal for each?

A

1) Elevated plus maze of cross
>Place the rodent in the centre of the cross
>Rodents will be scared to go via the open side of the cross, they will walk through the closed side

2) Light/ Dark box
>Open to daylight on one side, other side is in dark
>Rodents are afraid of predation so hide in the dark part of the box

3) Conflict test
>Associate a treat with a sound and a mild shock, so they want the treat but will be unformattable to get it.

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8
Q

What is the observed effect of giving anxiolytics to mice in an elevated plus maze of cross model?

A

They will walk on both the barrier (closed) and open side of the box.

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9
Q

What is the observed effect of giving anxiolytics to mice in a Light/ Dark box model?

A

The preference for the dark side of the box goes away and the mice walk on both the dark and the light side.

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10
Q

What is the observed effect of giving anxiolytics to mice in a Conflict Test model?

A

They will ignore the sound or shock and will go for the treat anyway.

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11
Q

What is the effect of treating the mice in models for stress with analgesics and anti-depressants instead of anxiolytics; what does this show?

A

> The mice will stop feeling the pain from a shock because of the analgesics but will still suffer from anxiety

> Shows the fear response is different from mechanisms involved in depression and pain

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12
Q

What do anxiolytics like Benzodiazepine target?

A

GABAA receptors (GABA = main inhibitory neurotransmitter in CNS)

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13
Q

What are the 2 binding sites on a GABAA receptor and what binds there?

A

1) Orthosteric site
>Where agonist like GABA bind

2) Allosteric site
>Where allosteric modulators bind

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14
Q

What 5 drugs bind to the allosteric site of GABAA receptors and are they safe to be taken taken together?

A

> Benzodiazepine, Ethanol, Barbiturate, Neurosteroids, Flumazenil

> When taken alone, these drugs are safe, but when combined is dangerous, e.g. combining one with alcohol.

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15
Q

How many subunits make up a GABAA receptor and what are the possible names?

A

> 5 subunits

> They contain alpha, beta or gamma subunits in different combinations depending on where the receptor is found in the brain.

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16
Q

When GABAA receptors are activated by GABA, what ion flows through and what is the effect of this?

A

Chloride ions flow into the nerve, making the membrane potential more negative (closer to Cl- Nernst potential) so less APs fire.

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17
Q

What are 3 ligands, other than GABA and general anaestehtics, which bind to the orthosteric site of a GABAA receptor and what type of drug are they?

A

1) Muscimol is selective agonist to this site

2) Bicuculline is a competitive antagonist

3) Picrotoxin is a non-competitive antagonist for this.

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18
Q

What is the effect of Bicuculline and Picrotoxin binding to GABAA receptors at the orthosteric site?

A

> Would cause anxiety and seizures

> As both are antagonists for GABAA, the inhibitory effect on the CNS is knocked out so unwanted APs fire.

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19
Q

What is an allosteric modulator and its function?

A

An allosteric modulator does not activate the receptor on its own, it modifies the behaviour of the receptor when an agonist is bound to the orthosteric site

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20
Q

What is the effect of Flumazenil on GABAA receptors and when could it be used?

A

> A competitive antagonist for the allosteric site preventing allosteric agonists from having effect.

> To reduce the effects of an overdose

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21
Q

What is the effect of Flumazenil on GABAA receptors and when could it be used?

A

> A competitive antagonist for the allosteric site preventing allosteric agonists from having effect.

> To reduce the effects of an overdose of an allosteric agonist

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22
Q

Why do we have differently structured GABAA receptors in different areas of the brain and why is this useful?

A

> Due to different combinations of alpha, beta and gamma subunits (always makes up 5 subunits overall).

> This helps us target drugs to specific subtypes and areas of GABBAA receptors in brain

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23
Q

What subunit must be present in a GABAA receptor so that benzodiazepines can bind?

A

Alpha 2 subunit

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24
Q

What are 5 physiological effects of Benzodiazepine binding to GABAA allosteric site?

A

1) Sedation/ Anxiolytic

2) Hypnosis (sleep)

3) Anterograde Amnesia
>Prevent memory of events experienced while under their influence

4) Anti-convulsant

5) Reduction of muscle tone
>Useful for surgery

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25
Q

What mediates the different physiological effects caused by GABAA receptors?

A

The different combinations of GABAA subunits trigger different physiological effects when an agonist binds.

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26
Q

What type of drug are Benzodiazepines to GABAA receptors and what does this mean?

A

> Positive allosteric agonist

> If BZ is added in presence of agonist on orthosteric site (GABA) the response to GABA is made bigger (more Cl- crosses the membrane)

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27
Q

If benzodiazepines bind to GABAA alone what is the effect?

A

Benzodiazepines are positive allosteric agonist, so if no agonist (GABA) is bound to the orthostatic site, no effect will occur.

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28
Q

What method is used to measure that benzodiazepines are positive allosteric modulators?

A

Single channel patch clamp recordings with GABA present with and without benzodiazepines to show the current is larger when benzodiazepines are bound.

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29
Q

What are the physiological effects of 1) Positive allosteric modulators (PAM) 2) Negative allosteric modulators (NAM) of GABAA receptors?

A

1) PAM (positive allosteric modulator) stabilize the receptor in state with increased affinity of orthosteric site for GABA, effectively causes leftward shift in concentration response curve.
>Easier for GABA to stay in the channel and not bounce off

2) NAM (negative allosteric modulators) Stabilize the receptor in such a state that has reduced affinity for GABA and therefore effectively remains closed/harder to open

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30
Q

What are a) Short acting b) Long acting c) Intravenous benzodiazepines used to treat?

A

a) Short acting compounds (short half-life) mainly used as sleeping tablets so is gone by the time they wake up.

b) Long acting drug useful for treating general anxiety, however is a sedative and muscle relaxant, so people have lower awareness, response time, sleepy so can’t drive

c) Intravenous diazepam used to treat status epilepticus

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31
Q

What are 3 adverse effects of Benzodiazepines?

A

1) Tolerance
>decreased responsiveness to a drug following continuous exposure

2) Misuse
>Takes 2 weeks to develop a physical dependence

3) Physical dependence characterized by withdrawal
>increased anxiety, insomnia, CNS excitability, convulsions

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32
Q

How can we decrease a) Tolerance b) Physical dependence characterized by withdrawal for Benzodiazepines?

A

a) may be overcome by increasing dose

b) withdrawal may be alleviated by using slower acting drug

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33
Q

What are 2 uses of Benzodiazepines for treating anxiety now a days?

A

> To treat Acute anxiety

> Co-administered with anti-depressants during stabilisation period

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34
Q

What are 5 other class of drug used as an alternative for Benzodiazepines, what are they used to treat and an example for each?

A

1) Beta blocker
>Propranolol stops sympathetic activity, blocks heart rate increasing

2) Anti-depressants
>SSRIs (selective serotonin reuptake inhibitors eg. sertraline) useful for generalized anxiety, phobias, ptsd and obsessive compulsive disorder.

3) Buspirone
>5-HT1A receptor partial agonist, generalized anxiety not phobias

4) Atypical antipsychotics
>generalized anxiety & ptsd eg. olanzapine

5) Anti-epileptic drugs
>generalized anxiety eg. pregabalin

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35
Q

What is an issue with Buspirone?

A

Effective drug but takes several weeks to feel therapeutic effect, so need a different drug to short short term anxiety while the effects develop.

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36
Q

What type of drug are lorazepam and zolpidem?

A

Short acting Benzodiazepines

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37
Q

What does an inverse agonist do?

A

Inverse agonist stabilizes a receptor so it doesn’t pop into spontaneously active state

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38
Q

What is spontaneous activity and how was it measured?

A

> A receptor randomly enters an active state due to their dynamic structure.

> Patch clamp data showed this.

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39
Q

Why can someone not drink alcohol while taking benzodiazepines?

A

As they are both positive allosteric modulators, the levels of CNS depression they cause on the active GABAA receptors adds up leading to death.

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40
Q

Why can you not die from overdose of Benzodiazepines alone?

A

> Drugs working as allosteric regulators only impact receptors occupied by agonist in an orthosteric site.

> Not every GABAA receptor in the brain is active at the same time, so cannot die from BZ high conc (only impact the neurons with GABA present).

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41
Q

Even though Barbiturates are positive allosteric modulators, how can someone still overdose on them and what is a clinical use for this?

A

> As conc increases they behave as an agonist for the orthosteric site so can activate more neurons while BZ cant. This means GABAA with no GABA present can be activated until death.

> Euthanasia for humans and in veterinary practice

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42
Q

What drug is used to treat epilepsy?

A

Anticonvulsants

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43
Q

What drug is used to treat epilepsy?

A

Anticonvulsants

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44
Q

How are seizures classified?

A

By how it spreads and the location of abnormal activity

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45
Q

What are a) Partial b) Generalised seizures?

A

a) The spread of the seizure is limited to a part of the brain.

b) The spread of the seizure involves both hemispheres of the brain.

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46
Q

What are a) Simple b) Complex seizures and how are these linked to partial and generalised seizures?

A

a) Simple = no loss of consciousness

b) Complex = loss of consciousness

> Both partial and generalised epilepsy can be simple and complex seizures (e.g. complex generalised seizures).

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47
Q

What method is used to diagnose epilepsy?

A

With EEG (electroencephalogram)

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48
Q

What is the main symptom of epilepsy?

A

Unprovoked seizures

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49
Q

What is the effect if a seizure involves a) Motor cortex b) Hypothalamus c) Reticular formation?

A

a) Gives rise to convulsions and contractions

b) Symptoms are associated with ANS discharge, e.g. excess salivation and sweating.

c) Makes someone unconscious

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50
Q

What is the effect of a generalised seizure?

A

The whole body could convulse and an immediate loss of consciousness as the whole of the brain can be involved in the seizure.

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51
Q

What is a seizure?

A

Sudden abnormal firing of action potentials in the brain.

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52
Q

What are 5 factors which can effect the occurrence of seizures?

A

1) Blood glucose levels

2) pH

3) Stress

4) Fatigue

5) High sensory input (e.g. flashing lights)

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53
Q

What mutation of a) NaV+ b) K+ channels can lead to epilepsy and why?

A

a) Gain of function mutations of NaV+ channels responsible for depolarisation giving rise to more APs firing.

b) Loss of function mutations for K+ channels which maintain the resting potential, means resting potential is more depolarised so more APs fire when they wouldn’t normally.

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54
Q

When performing an EEG how many electrodes must be placed on each hemisphere of the brain?

A

3

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55
Q

What 2 types of seizures can be classed as generalised seizures and what occurs in each?

A

1) Tonic-clonic seizures (grand mal)
>They happen in 2 stages – an initial “tonic” stage where you lose consciousness, shortly followed by a second “clonic” stage where full body convulsions occur.

2) Absence seizures (petit mal)
>Involves sudden lapses of consciousness that are so brief they don’t fall to the floor.
>Mainly occurs in children.

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56
Q

How can you tell an EEG reading is a generalised seizure instead of a partial seizure?

A

All generalised seizures cause all of the electrodes to have abnormal activity as both hemispheres are effected while a partial seizure would only effect some of the electrodes.

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57
Q

How can you tell if an EEG reading is a tonic-clonic type or an absence seizure type (both are generalised)?

A

> Tonic-clonic seizures involve unsynchronised abnormal activity and after this is a rhythmic firing, this causes rhythmic contractions/ relaxations of muscles (can last minutes)

> Absence seizures involve Unsynchronised abnormal activity occurs for a short period of time then returns to normal (shows oscillatory behaviour).

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58
Q

What are 2 methods a drug can take to treat epilepsy?

A

Either decrease excitatory neurotransmission or increase inhibitory neurotransmission.

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59
Q

What are 3 animal models used to better understand the neurobiological basis of epilepsy and evaluate anti-convulsant drugs and how do they work?

A

1) Chemical models
>Apply chemicals to cause seizures in animals.

2) Kindling model
>Apply low level electrical stimulus over a period of time, this animal develops a partial seizure in that area of the brain. (mimics a seizure)

3) Genetically modified animals
>Carrying mutations leading to epilepsy.

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60
Q

How are a) Penicillin b) PTZ c) Kainate used as chemical models to cause seizures?

A

a) Apply penicillin directly to brain block GABA receptors causing epilepsy

2) PTZ if added directly to water triggers seizures due to block of GABA (inhibitory neurotransmitter)

3) Kainate is agonist of glutamate (excitatory) receptors causing seizures

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61
Q

What are 3 ways anti-convulsant drugs can act on GABAA receptors to increase inhibitory neurotransmission and which is the most selective?

A

1) Agonist or positive allosteric modulator for GABAA receptor

2) Block GABA re-uptake so GABA stays in cleft for longer.

3) Inhibit GABA metabolism so GABA concentration increase.

> Last two will affect all GABA neurotransmission (less selective), while drugs acting at specific receptor may be somewhat more ‘selective’

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62
Q

What are 3 Benzodiazepines (PAM) used as anti-convulsant drugs and what is 3 issues with them?

A

> clonazepam, clobazam, diazepam

> Issues: sedation (sleepy), tolerance, withdrawal

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63
Q

How is diazepam administered and when is it used in terms of epilepsy?

A

Diazepam used intra-venus for status epilepticus (life threatening generalized never ending seizure), so is only used in desperate times

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64
Q

What are 2 barbiturates (PAM) used as anti-convulsant drugs and what is 3 issues with them?

A

> Phenobarbitone, primidone

> Issues: Small therapeutic index, sedation, complex pharmacokinetics

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65
Q

What is an example of a drug used to block GABA re-uptake?

A

Tiagabine

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66
Q

What are 2 drugs used to inhibit the metabolism of GABA, how do they work and what is the issues for both?

A

1) Vigabatrin
>Problems: depression

2) Valproate
>Problems: high protein binding, rarely hepatotoxic, teratogenic, and rare liver damage

> Both are suicide inhibitors for GABA Transaminase (enzyme which metabolizes GABA), so levels of GABA build up.

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67
Q

How is GABA synthesized and by which enzyme?

A

> Glutamate is made from a metabolite from the Krebs cycle.

> In GABAneric neurons GAD enzymes are present which convert Glutamate to GABA.

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67
Q

What are the 2 enzymes for GABA to be broken down?

A

1) GABA Transaminase (inhibited by Vigabatrin and Valproate) is activated.

2) Succinate semialdehyde dehydrogenase enzyme is activated as well and both metabolize GABA

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68
Q

What do a) Acetylation b) Methylation do and whta enzymes are used?

A

a) Acetylation of histone tails by histone acetyl transferases (HAT) leads to opening of the nucleosome chain which allows transcription factors (TF) to bind gene promoter regions on DNA and activate gene expression

b) DNA methylation by DNA methylases causes gene silencing by closing the nucleosome chain by HDAC enzymes which remove acetyl groups; so transcription factors can’t bind to gene promotor regions.

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69
Q

How does sodium valproate effect HDAC enzymes and is the effect on GABA?

A

> Sodium valproate inhibits HDAC enzymes, which remove acetyl groups from histones, causing the nucleosome chain to stay open from acetylation.

> This will increase transcription of GABA so can cause increased inhibitory effects.

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70
Q

What drugs can decrease excitatory transmission and therefore decrease chances of seizures and what is an issue with them?

A

> Use-dependent Na+ channel inhibitors

> Aren’t very selective so will effect Na+ channels found in nerves and muscles across the body.

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71
Q

Why do Na+ channels enter an inactive state after time has passed?

A

After a while Na channels enter inactivated state due to inactivating particle blocking it, they need to go through his stage to be able to reactivate.

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72
Q

How do use-dependant sodium channel inhibitors cause decreased excitatory action?

A

> Use-dependent sodium channel inhibitors binding prolongs the duration of the inactive state (keeps the inactivating particle blocking)

> Slows down the channel to transition back to resting state, reducing number of channels available to response to depolarisation.

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73
Q

Why do use-dependant sodium channel inhibitors effect overactive neurons more than normal functioning neurons and what is 2 advantages about this?

A

> An overactive neuron have more Na+ channels in an inactive state as they enter this state on and off while firing.

1) So other neurons in brain aren’t effected as much

2) Great for treating partial seizures as can target specific area.

74
Q

What are 3 examples of use-dependant sodium channel inhibitors and their issues and an advantage?

A

1) Phenytoin
>Problems: complex pharmacokinetics, vertigo, ataxia, headaches, rashes etc.

2) Carbamazepine: most widely used anti-epileptic
>Problems: microsomal enzyme induction, shouldn’t be combined with other drugs

3) Lamotrigine
>Problems: nausea, dizziness, ataxia, rashes

> Advantage for all is they are not a sedative

75
Q

What channel mediates absence seizures and what happens if they are inhibited?

A

> Absence seizures comes from a group of neurons that use T-Type Ca channels to mediate AP firing, this drives oscillatory behaviour in brain

> If these channels are inhibit absence seizures are stopped.

76
Q

How do both GABApentin and Pregabalin work and what do they treat?

A

> Both bind to α2δ subunit of T-type Ca2+ channels to reduce trafficking of channel to plasma membrane

> Treats absence seizures

77
Q

What is an example of a T-type Ca inhibitor and what is it used to treat?

A

> Ethosuximide

> To treat absence seizures

78
Q

How does Levetiracetam work?

A

Binds to a protein found on synaptic vesicles ,it is somehow involved in controlling glutamate levels in vesicles, so decreases amount of glutamate released from vesicles (limits glutamate transmission through presynaptic mechanism).

79
Q

What are 4 amine neurotransmitters in the CNS?

A
  1. Noradrenaline
  2. Dopamine
  3. 5-Hydroxytryptamine (Serotonin)
  4. Acetylcholine
80
Q

What is an overview to how anti-depressant drugs exert their action?

A

Anti-depressant drugs exert their actions by interfering with amine transmission

81
Q

What type of neurotransmitter is noradrenaline and dopamine and what is the effect of this?

A

> An aerosol neurotransmitter

> It is like an aerosol and spreads wide to effect many neurons around it (broad activity)

82
Q

Where are the main sources of neurons of noradrenaline and where do their processes extend to?

A

> Locus coeruleus

> Extend to innervate the cerebral cortex, hypothalamus, amygdala and cerebellum

83
Q

What receptor family do all the receptors that respond to dopamine and noradrenaline fall into?

A

G-protein coupled receptors.

84
Q

What are 3 types of adrenergic receptors found in the brain, what G-protein are they coupled to and what is their effect?

A

1) a1
>Through Gq proteins (increase phospholipase C signalling)
> Through cerebellum and cortex mainly
> involved in motor control, cognition, fear

2) a2
>Gi receptor (inhibits cAMP)
>Regulation of blood pressure, sedation and analgesia

3) b1
>Gs coupled receptor (signals through cAMP)
>in cortex, striatum and hippocampus
> contribute to long term effects of antidepressants

85
Q

What are the 3 dopamine signalling pathways?

A

1) Nigrostriatal pathway

2) Mesocortical and mesolimbic pathways

3) Tuberohypophyseal pathway

86
Q

What does the Nigrostriatal pathway control and in what disease is it effected?

A

> Fine motor control

> Degenerates In Parkinson’s

87
Q

What does the Mesocortical and mesolimbic pathways control and what does destruction of this pathway lead to?

A

> Drives behaviours like perseverance, pleasure-euphoria-reward (motivation), compulsion, and causes addiction.

> Destruction leads to stereotypical behaviour such as frantic pacing in animals

88
Q

Where are the cell bodies for the Tuberohypophyseal pathway found and what do they control?

A

> Cell bodies in hypothalamus

> Pituitary hormone secretion e.g. prolactin.

89
Q

What is side effects are caused by drugs targeting the Tuberohypophyseal pathway?

A

Hormonal side effects

90
Q

What is the function of the enzymes a) dopamine-b-hydroxylase b) Tyrosine hydroxylase c) DOPA decarboxylase?

A

a) Converts Dopamine to noradrenaline

b) Converts Tyrosine to DOPA

c) Converts DOPA to Dopamine

91
Q

What is the rate limiting enzyme in the synthesis of dopamine?

A

Tyrosine hydroxylase

92
Q

In terms of enzymes, what method can be used to tell if a neurons is dopaminergic or adrenergic?

A

Adrenergic neurons contain dopamine-b-hydroxylase as this converts dopamine into noradrenaline and then adrenaline. While dopaminergic neurons do not contain dopamine-b-hydroxylase.

93
Q

What effect does Parkinson’s Disease have on a patient’s dopaminergic neurons?

A

DA neurons are lost in the substantia nigra

94
Q

What is a treatment for Parkinson’s Disease and what is an issue with it?

A

> L-DOPA may be administered to increase DA synthesis/ conc as it skips the rate limiting enzyme Tyrosine hydroxylase

> This causes hallucinations and only works in early stages as when too many DA neurons have been degraded, increasing dopamine conc won’t help.

95
Q

Why is it difficult to make a highly selective drug for dopaminergic and adrenergic receptors?

A

As adrenaline, noradrenaline and dopamine have very similar structures so can all bind to similar receptors.

96
Q

What 2 enzymes terminate dopamine action and where are they found?

A

1) COMT/ Catechol-O-methyltransferase

2) MAO/ Monoamine oxidases

> Both found extracellularly and intracellularly

97
Q

Other thane enzymes, what other proteins terminate action of dopamine?

A

Action of re-uptake transporters

98
Q

What does the drug Reserpine act on, what is the effect and when would it be used?

A

> Blocks amine neurotransmitter storage (dopamine) storage, leads eventually depletion

> Counteracts amphetamines and decreases positive schizophrenic symptoms.

99
Q

What method can be used in clinic to measure if there are defects in dopaminergic transmission?

A

Measure the levels of the 2 main products of dopamine metabolism: DOPAC (Dihydroxyphenylacetic acid) and HVA (Homovanillic acid)

100
Q

What are the 2 families of dopaminergic receptors and what separates them?

A

> Divided by the type of G protein they commonly associate with.

1) D1, D5
>are Gs coupled receptors, stimulate adenylyl cyclase

2) D2, D3, D4
>are Gi coupled receptors

101
Q

What is the effect of stimulating D1 or D5 dopaminergic receptors?

A

> As they are Gs coupled, stimulates adenylyl cyclase.

> Increase cAMP, PKA and protein phosphorylation

102
Q

Where are D1 dopaminergic receptors commonly found and for what disorder are they targeted for?

A

D1 found a lot in cortex, drug target for schizophrenia.

103
Q

What is the effect of stimulating D2 , D3 or D4 dopaminergic receptors?

A

> As are Gi coupled, inhibit adenylyl cyclase, lowering cAMP

> Activate potassium channels inhibiting action potential firing.

> And Inhibits VGCC (voltage gated calcium channels) so Ca influx into neurons decreases.

(Opposes D1 receptor activation).

104
Q

As well as on dopaminergic neurons, where else are D2 receptors found and what is their function?

A

> D2 receptors found on pituitary cells

> Regulate prolactin release (inhibition of D2 in this pathway increases prolactin secretion)

105
Q

Why is it hard to have a drug which is selective to certain dopaminergic pathways?

A

As each dopaminergic neurons has many different types of dopaminergic receptors.

106
Q

How do Amphetamines work and the effects of dopamine and noradrenaline?

A

> Act as a false transmitter; taken up into vesicles storing amine neurotransmitters causing the neurotransmitter to increase conc in cytosol until the conc gradient favours exit of amines out of cell instead of reuptake

> This increases NA and DA signalling as more is in the cleft until stores are depleted.

107
Q

What factor are amphetamines independent of?

A

Action potential firing does not effect the drug as they effect the storage of amine neurotransmitters in vesicles.

108
Q

How does cocaine work and what are its effects?

A

> An inhibitor of reuptake transporters, so amine neurotransmitters are not effectively taken back up so stay in the cleft for longer.

> Leads to increased motor activity in SNS and PNS . Extreme cases can cause agitation and can cause cardiovascular collapse.

109
Q

Why are both amphetamines and cocaine addictive?

A

As both lead to activation of reward pathways and euphoria

110
Q

What percentage of people over 18 have schizophrenia?

A

1.1%

111
Q

What are the 2 categories of symptoms for people suffering from schizophrenia and who’s is more likely to suffer from both?

A

1) Positive symptoms
>Younger people

2) Negative symptoms
>Older people

112
Q

What are examples of positive symptoms of schizophrenia?

A

Hallucinations (voices), delusions (paranoid), thought disorders (irrational/wild, delusions of grandeur, garbled sentences) ,
defects in selective attention, bizarre behaviour, aggression, stereotyped movements, catatonia

113
Q

What are examples of negative symptoms of schizophrenia?

A

Blunting of emotions, withdrawal from social contacts, flattening (unresponsive) of emotional responses, anhedonia (don’t get happy anymore), reluctance to perform everyday tasks.

114
Q

What may positive symptoms of schizophrenia be accompanied with?

A

Cognitive deficits (attention, memory), anxiety, depression, self punishment leading to suicide attempts (50% cases)

115
Q

What are 2 classes of factors which can cause schizophrenia?

A

1) Hereditary
>A range of genes can be effected causing lack of neuronal development.

2) Environmental
>Consumption of cannabis in adolescence

> A genetic predisposition combined with environmental factors increases chances drastically.

116
Q

How can drugs increase and decrease schizophrenia-like symptoms?

A

Drugs that enhance DA signalling increase positive schizophrenia-like symptoms, D2 blocking drugs reduce them

117
Q

How do Ketamine and LSD cause positive schizophrenic symptoms and what does this show?

A

> As Ketamine is an NMDA antagonist and LSD exerts actions as agonist of serotonin receptor (5 HT2A)

> This shows it is not just dopamine involved in causing schizophrenia but is glutamate and serotonin is too.

118
Q

What pathway is effected to cause a) positive b) negative schizophrenic symptoms and what receptor is effected in each?

A

a) Overactivity of Mesolimbic pathway associated with +ve symptoms
> Increased D2 activity

b) Decreased activity in Mesocortical pathway Associated with –ve symptoms
>D1 receptors implicated

119
Q

Why is schizophrenia hard to treat with drugs?

A

As we need an antagonist for D2 positive symptoms but also need a D1 agonist to decrease negative symptoms and it is hard to make a dopaminergic drug selective.

120
Q

What positive symptom of schizophrenia do amphetamines, L-DOPA, and D2 receptor agonists cause?

A

Hallucinations

121
Q

What % occupancy do D2 receptor antagonists need to reach for the positive symptoms of schizophrenia to decrease?

A

80% occupancy

122
Q

What 2 factors can increase the positive symptoms of schizophrenia?

A

1) Increasing dopamine activity

2) Decreasing glutamate activity (downregulate NMDA receptors)

123
Q

What are the 2 types of Antipsychotic drugs and what issues and benefits do they have?

A

1) First Generation Antipsychotics (Typical or neuroleptics)
>Had severe side effects causing motor disturbances, Parkinson’s like symptoms, also caused prolactin secretion even in males

2) Second generation Antipsychotics (atypical)
>Beneficial as targets the mesocortical pathway whiole avoiding the Nigra striatal (motor control) and neurohypophysial (endocrine control) pathways minimising side effects.

124
Q

What are 2 examples of a) First Generation Antipsychotics b) Second Generation Antipsychotics

A

a) chlorpromazine, haloperidol

b) clozapine, risperidone

125
Q

What are 8 unwanted side effects of antipsychotic drugs?

A

1) Parkinson’s like symptoms, Acute reversible dystonias

2) Slowly developing irreversible tardive dyskinesia (involuntary movements)
>Irreversible

3) Increased prolactin release

4) Sedation,

5) Hypotension,

6) Weight Gain

7) Dry mouth,

8) blurred vision

126
Q

What is the effect on drugs that amine neurotransmitters (DA, NA and adrenaline) have a very similar structure?

A

> Drugs will bind to a combination of amine receptors.

> What defines the drug isn’t which receptor it binds to, it the specific combination of amine receptors it binds to

127
Q

What are the 2 classifications of depression and what is their difference?

A

1) Unipolar depression
>mood swings always in same direction

2) Bipolar depression
>Experiences mood swings in any direction.

128
Q

What are the 2 subcategories of Unipolar depression, what causes them and what percentage of the patients have them?

A

1) Reactive unipolar depression
>Caused by life events
>75%

2) Endogenous unipolar depression,
>cannot identify a cause
>25%

129
Q

Is the pharmacology to treat Unipolar and Bipolar depression different?

A

Yes, different drugs are required.

130
Q

What are 4 symptoms of unipolar depression?

A

1) low mood (anhedonia= inability to take pleasure)

2) apathy: loss of interest in daily activities

3) severe loss or gain in weight/appetite

4) low self-esteem, feelings of worthlessness or guilt

131
Q

What are 3 symptoms of unipolar depression?

A

1) Sleep disturbance: insomnia or excessive sleeping

2) loss of appetite & libido

3) diminished ability to think/concentrate

132
Q

What is a subjective-qualitative diagnosis for depression?

A

Patients exhibit depressed behaviour for >2 weeks and symptoms disrupt normal social and occupational function then they are diagnosed with depression.

133
Q

What are 3 risk factors for unipolar depression?

A

1) Stressful life events (personal loss, financial or professional crisis)

2) Genetic risk ~40%

3) Secondary to illness (e.g. Cushing’s from steroid use) side effect of a drug

134
Q

What 4 areas of the brain are effected in patients with depression and what are these areas involved in?

A

1) Cingulate nucleus linked to development of depression

2) Nucleus succumbence uses dopamine which increases neuronal activity which increases BDNF ( Brain-derived neurotrophic factor)

3) Amygdala involved in emotion

4) Hippocampus important for memory and learning behaviour

135
Q

How is anxiety linked to depression?

A

High levels of cortisol (hormone associated with stress) decreases the CREB (transcription factor) activity which intern decreases the concentration of BDNF ( Brain-derived neurotrophic factor)

136
Q

What 2 peptides are altered in patients with depression and what is the effect of this?

A

hormones normally associated with feeding behaviour (Ghrelin and Leptin) these are disrupted which causes abnormal feeding behaviour.

137
Q

Are men or women more susceptible to depression?

A

Women

138
Q

What is postnatal depression?

A

Depression which occurs in women usually 2-8 weeks after delivery and in some cases stays even a year after the birth of the baby.

139
Q

How does postnatal depression effect the child of a mother and why?

A

> Children of mothers who develop postnatal depression, are more likely to be susceptible to depression later in life

> Due to epigenetic changes occur in the new born as a result of the reduced normal interactions with their mother because she is depressed.

140
Q

What are 2 animal models to help us understand the chemical change depression causes and what do they test?

A

1) Acute stress models
>Tests the coping behaviour and despair when an animal is in a stressful environment one time.

2) Chronic stress models
>Tests the transcriptional and epigenetic changes of animals in prolonged and repeating stressful situations.

> Both mimic human depression in mice.

141
Q

What is an example of an acute stress model, what is the effect of giving anti-depressant drugs?

A

> Put small rodent into a pool of water and measure how long they try to escape and when they give up

> With anti-depressants they don’t give up for longer.

142
Q

Why don’t acute stress models using rodents match the depression of humans?

A

These short term animal models don’t fully replicate human depression as in humans if we give these same anti-depressant drugs we don’t see effects till 6 weeks but in animal is immediate.

143
Q

What drugs does an acute stress model test the efficacy of the best?

A

monoaminergic antidepressant drugs.

144
Q

What is an example of an Chronic stress model, what is the effect of giving anti-depressant drugs?

A

> Applying shock to animals feet and they don’t try to move away eventually due to learned helplessness, if we treat with drugs like analgesics they still don’t try get away

> Anti-depressants will reduce the learned helplessness so the mice will try move for longer.

145
Q

How do antidepressants decrease learned helplessness?

A

Firing patterns in periaqueductal grey fire abnormally when learned helplessness is achieved, when treated with anti-depressant drugs this firing activity returns back to normal and we see changes in expression of transcription factors like FOS

146
Q

What is the Ventral tegmental region of the brain involved in?

A

Involved in regulating reward pathways

147
Q

What 3 neurotransmitters are involved with depression and how?

A

1) Noradrenaline & 5HT (serotonin)
>NA and 5HT have long term trophic effects on neuronal survival as well as short term effects

2) BDNF acting on TrkB receptors
>Depressed people produce less of the Trophic factor BDNF so less TrkB receptors are activated resulting in less neurogenesis (less new neurons made).

3) Glutamate through glutamatergic (NMDA) receptor neurodegeneration.
>Overtime successive overactivation of NMDA receptors can contribute to neurodegeneration.

148
Q

Why do anti-depressants take weeks to effect humans?

A

As the monoamine hypothesis discuses, noradrenaline and serotonin (5HT) have long term trophic effects in neuronal survival as well as short term effects, so monoamine drugs will take a while to have effect.

149
Q

What is a trophic factor?

A

A molecule that allow a neuron to develop and maintain connections with its neighbours

150
Q

What 3 areas of the brain contribute to depression and what monoamine neurotransmitter are they involved in the transmission of?

A

1) Locus coeruleus
>main source of NA in brain

2) Ventral tegmental area
>Involved with dopamine transmission

3) Raphe nucleus
>Involved with serotonin transmission

151
Q

In terms of monoamine neurotransmitters, what a) alleviates symptoms of depression b) leads to symptoms of depression?

A

a) Stopping the breakdown or re-uptake of monoamine neurotransmitters alleviates symptoms of depression

b) Increasing depletion of monoamine neurotransmitters leads to symptoms of depression

152
Q

How does a) Iproniazid b) Reserpine c) Tricyclic antidepressants work and what is their effect on the symptoms of depression?

A

1) Iproniazid, is an MAO (monoamine oxidase enzyme for metabolism of amine neurotransmitters) Inhibitor
>As MAO is inhibited, monoamine neurotransmitters increase in conc, alleviating depression symptoms.

2) Reserpine depletes vesicles of monoamine neurotransmitters.
>This depletion causes development of depression and Parkinson’s symptoms

3) Tricyclic Antidepressants inhibit re-uptake of monoamine neurotransmitters 5-HT (serotonin) and/or NA (noradrenaline)
>This treats the symptoms of depression as inhibits the re-take up of monoamine neurotransmitters

153
Q

What is a sub-anaesthetic dose of ketamine used to treat and when would it be used?

A

Ketamine are good anti-depressants especially in individuals resistant to other medications

154
Q

What is a supporting argument in favour of the monoamine hypothesis of depression?

A

As drugs which stop the breakdown or re-uptake of monoamine neurotransmitters alleviates symptoms of depression, while depletion of monoamine neurotransmitters leads to symptoms of depression.

155
Q

What are 4 different classes of anti-depressant drugs?

A

1) Monoamine oxidase inhibitors

2) Classical Tricyclic antidepressants

3) Selective serotonin(5-HT) reuptake inhibitors

4) Monoamine Receptor Antagonists

156
Q

What are 3 examples of Monoamine oxidase inhibitors and type of inhibitor are they?

A

> Phenelzine, irreversible inhibitor

> moclobemide, Reversable inhibitors

> Iproniazid, irreversible inhibitor

157
Q

What is an example of a Classical Tricyclic antidepressants and how do they work?

A

> imipramine

> Will block re-uptake so all monoamine neurotransmitter (not selective) remains in synapse for longer.

158
Q

What is an examples of a Selective serotonin (5-HT) reuptake inhibitors and how do they work?

A

> SSRIs e.g. fluoxetine, (Prozac)

> Decreases reuptake of serotonin (is selective unlike Classical Tricyclic antidepressants)

159
Q

What are the 2 types of monoamine oxidase enzymes (MAO) and what drugs target which types and why??

A

1) Type a
>Type a is preferred form for noradrenaline and 5-HT breakdown so anti-depressants tend to selectively inhibit type a to increase NA and 5HT conc

2) Type b
>Type b selective inhibitors are useful for treating Parkinson’s

160
Q

How is postural hypotension (low blood pressure from lying down) caused by type a monoamine oxidase inhibitors?

A

NA depletion caused in sympathetic terminals causes postural hypotension (low blood pressure) as NA increases blood pressure when present.

161
Q

Why can’t patients taking type a monoamine oxidase inhibitors eat much cheese?

A

As cheese is rich in Tyramine (amino acid), as their MOA enzymes are inhibited which breaks down Tyramine, they will have too high levels of Tyramine and be transported into sympathetic neurons by amine transporters and will act to displace noradrenaline from vesicles causing NA leaking independent of action potentials leading to hypertension.

162
Q

What is different between old Tricyclic anti-depressants and SSRIs (Selective serotonin reuptake inhibitors)?

A

SSRIs specifically inhibit 5-HT reuptake less side effects & toxicity. While old TCAs had little selectivity between NA and 5-HT channels

163
Q

What is different between old Tricyclic anti-depressants and SSRIs (Selective serotonin reuptake inhibitors)?

A

SSRIs specifically inhibit 5-HT reuptake less side effects & toxicity. While old TCAs had little selectivity between NA and 5-HT channels

164
Q

What issue causes unwanted side effects while using monoaminergic anti-depressant drugs?

A

Side effects due to monoamine neurotransmitters having similar chemical structures so we have off target effects on different monoamine receptors.

165
Q

While using monoaminergic anti-depressants, what 3 off target systems can be effected and what unwanted symptoms does this cause?

A

1) Activation of anticholinergic system (mACh receptors)
>dry mouth, blurred vision, constipation

2) Blocking a2 receptors, adrenergic system
>postural hypotension/ feel faint when stand up

3) H1 receptors blocked, histaminergic system
>Causes sedation

166
Q

What is the effect of inhibiting noradrenaline re-uptake (NARIs) in the frontal cortex?

A

Improves mood.

166
Q

What is the effect of inhibiting noradrenaline re-uptake (NARIs) in the frontal cortex?

A

Improves mood.

167
Q

Where are most of the cell bodies for Serotonergic pathways in the CNS found?

A

In the Raphe nuclei

168
Q

What are 5 uses of drugs acting on 5-HT (serotonin)?

A

Drugs acting on 5-HT transmission are used to treat depression, anxiety, migraine, anti-emetic (chemotherapy as serotonin receptors control vomiting), antipsychotic (schizophrenia)

169
Q

What aspect of depression does serotonin (5-HT) control?

A

5-HT role in regulating limbic processing relates it to anhedonia: the inability to gain pleasure from normally pleasurable experiences

170
Q

Why does eating Tryptophan rich foods decrease symptoms of depression?

A

As synthesis of 5-HT starts from amino acid Tryptophan (essential amino acid), so many anti-depressants contain Tryptophan to directly add serotonin to the brain.

171
Q

How many subfamilies of receptors for serotonin (5-HT) are known of?

A

7

172
Q

What type of receptor are each of the 7 subfamilies of serotonin receptors, and which is most commonly targeted by anti-depressant drugs?

A

> 5HT3 is the only ligand gated one, rest are all GPCRs,

> 5HT1A and 5 couple to gi/go, Inhibitory GPCRs, important target for anti-depressant drugs.

> 5HT2 is Gq coupled,

> 5HT 4,6,7 Are Gs coupled

173
Q

What receptors does LSD (psychedelic) target and what is the effect?

A

> 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist

> Serotonin receptor activation causes hallucinations

174
Q

What are the effects on a patient with depression when taking a drug which increases 5HT1A receptor levels?

A

> When we take a drug increasing levels of 5HT1A, initially causes decrease in neurotransmission, so their depression actually gets worse as brain levels of 5-HT go down

> Over the course of 6 weeks, these receptors become desensitized and neuron gets rid of these inhibitory receptors which increases neuronal activity, so 5-HT release and function increases; so depression symptoms lower.

175
Q

What is the function of 5HT1A serotonin receptors?

A

These inhibitory 5HT1A receptors inhibit neurotransmitter release, inhibit serotonin release and inhibit action potential firing.

176
Q

What does increased activation of a neuron lead to?

A

Increased activation of a neurons leads to increased activation of the transcription factor CREB which causes increased BDNF production, this stabilizes synapses.

177
Q

What is the difference between a normal person’s synapse and a depressed person’s?

A

> Very active synapses, postsynaptic neuron releases BDNF which stabilizes presynaptic site

> In depressed people, reduced activity loses BDNF stabilization so synapse is lost

178
Q

Why does boosting serotonin levels lead to less synapses being lost?

A

When we boost serotonin levels, this boosts activity for a neuronal network, this causes increased BDNF production so the neuron is stabilized

179
Q

What is a non-chemical method to treat unipolar depression?

A

Electroconvulsive shock therapy, give treatment to specific brain areas to effect amine transmission

180
Q

What is a common drug used to treat bipolar depression and how does it work?

A

Lithium works through different mechanism, enters through hyperactive Na channels on neurons to regulate activity of downstream signalling contributing to bipolar depression

181
Q

Despite both benzodiazepines and barbiturates being positive allosteric modulators for GABAA receptors, how is their mechanism of action different?

A

Benzodiazepine agonists increases frequency of openings, while barbiturates another allosteric regulator, increases duration of openings

Pharmacology Year 2 (8 decks)

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