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Integrated Physiology and Pharmacology > CNS Pharmacology > Flashcards

CNS Pharmacology Flashcards

1
Q

What is generalised anxiety?

A

Anxiety for no clear reason or focus, symptoms interfere with normal productive behaviour

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2
Q

Name two excitatory amino acids

A

Glutamate and aspartate

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3
Q

Name two inhibitory amino acids

A

GABA and glycine

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4
Q

What can receptors be determined by? (7 things)

A 
Subunits
Composition
Pharmacology
Time course
Calcium permeability
Distribution
Neuronal function
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5
Q

What are the two main types of GABA receptors (based on their function)?

A

Ionotropic - NMDA, AMPA, Kainate and Delta (GABAa)

Metabotropic - GPCRs (GABAb)

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6
Q

What is the pathway for GRPI to activate PkC?

A

GQ increases -> PLC -> IP3 -> DAG -> PkC

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7
Q

What is the pathway for GRPII/III to activated potassium channels?

A

Gi/o decreases -> adenyl cyclase -> NaV -> activated potassium channels

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8
Q

What type of transmission does GABAa receptors mediate?

A

Fast inhibitory

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9
Q

GABAa receptors are selective to what ion?

A

Chloride

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10
Q

What is the agonist for the GABAa receptor at the orthosteric site?

A

Muscimol

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11
Q

What are the two antagonists for the GABAa receptor at the orthosteric site?

A

Bicuculline and pictrotoxin

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12
Q

What is the agonist for GABAa at the allosteric site?

A

Diazepam

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13
Q

What is the antagonist for GABAa at the allosteric site?

A

Flumazenil

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14
Q

What is the agonist for GABAb receptors?

A

Baclofen

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15
Q

What is the antagonist for GABAb receptors?

A

Phaclofen

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16
Q

What do GABAb receptors inhibit and what is the effect of this?

A

Voltage gated calcium channels = pre synaptic inhibition

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17
Q

What do GABAb receptors activate?

A

Potassium channels (GIRK) producing post synaptic inhibition

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18
Q

What is meant by constitutive activity?

A

Where the channels open in the absence of an agonist

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19
Q

What is betacarpaline?

A

An inverse agonist which stabilises the closed formation of channels, stopping occasional opening

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20
Q

What do allosteric binding sites do?

A

They modify the activity of a receptor to an agonist

In isolation they do not cause activation of the receptor eg they can not cause an overdose

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21
Q

What are the GABAa receptors targets for?

A

Sedatives, Anxioloytics, hypnotics, anti-convulsants, neurosteroids and some general anaesthetics

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22
Q

What are the subunits of the GABAa receptor?

A

2 alpha
2 beta
1 gamma or delta or epsilon

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23
Q

Where is the allosteric binding site in the GABAa receptors?

A

Between the alpha and gamma subunit

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24
Q

Which GABAa receptors are sensitive to benzodiazapine?

A

The gamma subunit must be present
Have to have alpha subunit of type 1, 2, 3 and 5 (4 and 6 are insensitive)
The difference is to one change in the amino acid sequence

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25
Q

Describe the experiment performed with mice which shows the effect of changing the alpha 2 subunit in the GABAa receptor

A

The wildtype mouse has normal alpha 2 subunit
The mutant mouse has mutated alpha 2 subunit (hist to threo)
In the light dark test:
1) Normally the mouse will hide in the dark box
2) Mice treated with diazapem will not hide
3) A knock-in mouse however does not show this effect and still hides

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26
Q

What are the physiological effects of benzodiazapine agonists (5 things?)

A 
Sedation/anxioloytics
Hypnosis
Anterograde amnesia
Anti-convulsants
Reduction of muscle tone
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27
Q

What is hypnosis?

A

The latency of sleep onset increases, the duration of stage 2 (non-REM) sleep is increased and the duration of REM is decreased
Duration of slow wave sleep (associated with sleep walking and night terrors) is decreased

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28
Q

Which two drugs can cause anterograde amnesia?

A

Flunitrazepam and rohypnol

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29
Q

How do benzodiazapines increase the chloride currents across the membrane?

A

They can increase the frequency of channels opening
They can increase channel open time
They can decrease channel close time
They can increase channel conductance

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30
Q

What can drug half life be dependent on?

A

Renal function
Age
Microsomal enzyme induction

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31
Q

What is an active metabolite?

A

Results when a drug is metabolised by the body into a modified form which continues to produce effects in the body.
Usually these effects are similar to those of the parent drug but weaker, although they can still be significant

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32
Q

How man types of benziodiazapimes are there?

A

60

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33
Q

Why might zoipodem be prescribed?

A

Short half life
No active metabolites
Good for insomnia

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34
Q

Why might diazapam be prescribed?

A

Good for generalised anxiety
Long duration of action/ long half life
No heavy sedation
Produces active metabolites

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35
Q

What can be the adverse effects of benzodiazapine agaonists?

A 
Sleepiness
Impaired psychomotor function
Amnesia
Additive effects with other CNS depressants can be fatal in over dose
Tolerance
Misuse
Physical dependence
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36
Q

What is tolerance?

A

Decreased responsiveness to a drug following continuous exposure

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37
Q

How can tolerance be overcome?

A

Increasing the dose

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38
Q

What is physical dependence characterised by?

A

Withdrawal symptoms eg Increased anxiety, Insomnia, CNS excitability and convulsions

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39
Q

Which drug is physical dependence more problematic with?

A

Triazolam - may cause day time anxiety when used to treat sleep disorders

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40
Q

What are the possible causes of epilepsy?

A 
Head injury
Local leisures
Neoplasms in humans
Infection
Genetic
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41
Q

Describe grand-mal (generalised) seizures

A

Complete loss of control
Tonic - clonic like; rhythmic contraction and relaxation
Reticular formation controlling consciousness is lost
2 phases - 1) Rapid action potential firing and 2) Tonic-clonic seizures

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42
Q

Describe petit-mal (generalised) seizures

A

Absence of seizure type
Found in children
No fill contraction but they show on/off attention
Brain wave activity is distinct - rhythmic oscillations
Usually due to mutations in voltage gated calcium channels

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43
Q

What are partial seizures?

A

Not all brain regions are affected
The hypothalamus is affected - impact on the ANS so patients may show increased salivation and urination etc
Reticular formation is affected = loss of consciousness
Patients report a sensation before the seizure
Other changes may cause a seizure; blood glucose, pH change, stress and fatigue, flashing lights

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44
Q

What happens if neurons fill with too much calcium?

A

They die by apoptosis

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45
Q

What is status epilacticus?

A

A medical emergency where a generalised seizure has lasted longer then 2 minutes

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46
Q

What drug is given to stop a sezuire?

A

Diazapine

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47
Q

What are the 3 possible targets for anti-epileptic drugs?

A

1) Targeting GABAa receptors on the post-synaptic membrane
2) Stopping GABA uptake mechanisms
3) Inhibiting GABA metabolisms in the pre-synaptic neuron

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48
Q

Which ant-epileptic drugs increase GABA transmission?

A

Benzodiazapines eg clonazapem, clobazam and diazepam
Uptake inhibitors such as tiagabine
Metabolic inhibitors such as vigabitrin and valproate

49
Q

What could be problems with using benzodiazapines to treat epilepsy?

A

Low therapeutic index, Sedation and complex pharmacokinetics

50
Q

What can vigabitrin cause?

A

Depression

51
Q

What type of cell has a role in regulating amino acid transimitter functions in the CNS?

A

Astrocytes

52
Q

Which cell process makes glutamate?

A

The Krebs cycle

53
Q

How is glutamate made?

A

In the Krebs cycle alpha-oxoglutarate -> glutamate -> glycine

54
Q

Which enzyme converts glutamate to GABA?

A

Glutamic acid decarboxylase (GAD)

55
Q

Neurons expressing GAD are what type of neurons?

A

Inhibitory as they can make GABA

56
Q

Which drug increases levels of GAD and thus GABA?

A

Valproate

57
Q

How is GABA broken down?

A

Broken down by 2 enzymes

1) GABA transaminase makes succinate semialdehyde
2) Succinate semialdehyde dehydrogenase then breaks down SS to make succinate which then enters the Krebs cycle

58
Q

What are the epigentics related to valproate?

A

Methylation of DNA - scrunches up DNA to repress transription
Acetlyation of histones - DNA opens up for transcription factors to bind
Valproate inhibits the action of de-acetylase enzyme so transcription of enzymes such as GAD increases

59
Q

Anti-epileptic drugs which target the excitatory synapse do what?

A

Block excitatory transmission at focus and limit the spread of epileptiform activity with use dependent sodium channels
They inhibit NaV responsible for action potentials

60
Q

What are the three states that sodium channels can exist in?

A

1) Closed
2) Open (controlled by voltage)
3) Inactivated

61
Q

Which state of NaV channels do anti-epileptic drugs stabilise?

A

The inactivated state - delayed return to the closed state, limiting the frequency of action potentials
The drugs only work on active channels

62
Q

Which anti-epileptic drugs are used to stabilise the inactivated state of NaV channels?

A

Phenytoin
Carbamazepine
Lamotrigine

63
Q

What could be the potential problems with using phenytoin?

A

Vertigo, ataxia, headaches, rashes

64
Q

What could be the potential problems with using carbamazepine?

A

Microsomal enzyme induction, shouldn’t be combined with other drugs

65
Q

What could the potential problems with using lamotrigine?

A

Nausea, dizziness, ataxia and rashes

66
Q

Where are transient (T) voltage gated calcium channels highly expressed?

A

Raph nucleus

67
Q

What is ethosuximide used to treat?

A

Absence seizures

68
Q

What does GABA-pentin do?

A

Acts as a subunit of the calcium channels which regulates its trafficing to the membrane
Affects other voltage gated channels
Analgesic

69
Q

What is levetiracetam?

A

Has a distinct drug target on synaptic vesicles (SV 2)
When associated with SV2 it impacts on loading vesicles with glutamate
pre-synaptic effect

70
Q

What us unipolar depression?

A

Causes are reactive (75%) or endogenous (25%)

71
Q

What is bipolar depression?

A

Manic depressive disorder, has a genetic link

72
Q

What are some of the symptoms of depression?

A

Low mood (anodonia), Negative thoughts eg suicide, Pecimism, Irritability, Loss of interest in activities, Sleep disorders, Loss of appetite, Difficulty concentrating, Low self-esteem

73
Q

How many people suffer from depression at some point in their lives in the USA?

A

1 in 6

74
Q

What brain regions can be complicated in depression?

A

The singular cortex
Nucleus sucumbuns (part of the limbic system)`
Amygdala
Hippocampus

75
Q

What has been observed in the nucleus sucumbuns

A

Increased activity with respect to trophic factor BDNF
Arises from input pathway (ventral tegmental area)
Receptors are TrkB

76
Q

What is the amygdala important for?

A

Procesing fear responnses eg in response to a scar face

77
Q

In the hippocampus a stress response causes a decrease in what?

A

BDNF signalling

78
Q

How are peripheral hormones complicated in depression?

A

Effected metabolism eg gehrin and leptin
Effects centrally on the hippocampus
Shows why there is a link between depression and eating disorders
The adrenal gland - part of the HPA cortex responsible for release of adrenaline

79
Q

What is postnatal depression and how can it affect children?

A

Occurs in mothers 6 weeks after birth
Causes the mother to neglect the child
Babies brainwaves can be altered if the mother is depressed so they are more likely to be depressed later in life

80
Q

What three techniques can be used to make an animal depressed?

A

Forced swim test
Suspension from tail
Immobilisation

81
Q

Which hormone is associated with depression?

A

cortisol (stress hormone)

82
Q

What is the monoamine hypothesis?

A

Serotonin and or adrenaline
Drugs increasing levels of these have anti-depressant properties
Idea was depression simply reduced monoamines

83
Q

What are the long term trophic effects of depression?

A

BDNF/TrkB has an effect on neurogenesis and synapse formation which is lowered in depression

84
Q

Increased activation of glutamate receptors causes what?

A

Excess activation = neuronal apoptosis

85
Q

Ketamine in low doses acts as what?

A

An anti-depressant (antagonist for NMDA receptors)

86
Q

What is Iproniazid?

A

The first specific antidepressant

MAO inhibitor

87
Q

What is reserpine?

A

Produces depression and parkinsonism, depletes stores of monamine transmitters

88
Q

What are MAOIs?

A

Inhibit monoamine oxidases so neurotransimitters remain present

89
Q

What are the three main classes of antidepressants?

A

1) Selective serotonin reuptake inhibitors
2) Classic tricyclic antidepressants
3) Monoamine oxidase inhibitors

90
Q

What are SSRIs?

A

Block serotonin being taken up so receptors for serotonin are stimulated more
Highly specific to serotonin
Eg fluoxetine

91
Q

What is an example of a classic tricylic antidepressant?

A

Imipramine

92
Q

What is a tricylic antidepressant?

A

They are named after their chemical structure, which contains three rings of atoms
Inhibit the reuptake of serotonin and noradrenaline

93
Q

Name two examples of MAOs

A

Phenylzine, moclobemide

94
Q

What are the side effects of MAOs?

A

Increased sympathetic discharge in the periphary = hypertension

95
Q

Which enzyme does MAO inhibit?

A

MAO type A

96
Q

What are the side effects of MAOs?

A

Anticholinergic; dry mouth, blurred vision and constipation
Adrenergic; Alpha-adrenoreceptor blocked, postural hypertension
Histaminergic; H1 block, sedation

97
Q

List examples of TCAs

A

Imipramine, Amitryptyline, clomipramine

98
Q

Why are overdoses in TCAs dangerous?

A

Confusion, mania, cardiac dysrhythmia

99
Q

What is fluexetine also known as?

A

Prozac

100
Q

What are the two types of NA receptors in the somadendritic regions and what is their action on serotonin?

A

Alpha 1 - Increases 5HT

Alpha 2 = inhibits release of 5HT

101
Q

Which receptor does Buspirone target?

A

5HT1A

102
Q

Where are the most serotonin neurons found?

A

In the raphe nucleus

103
Q

What is the precursor for 5HT?

A

Tryptophan

104
Q

Name the main SSRI

A

Prozac

105
Q

How does serotonin increase BDNF?

A

It works on cAMP = pKa activated = CREB (TF) = control of BDNF

106
Q

How does lithium work to treat bipolar?

A

It permeates NaV channels - inhibits inositol )controls calcium signalling), AKT signalling and glycogen synthase kinase 3 signalling

107
Q

Which antiepileptic drugs can also be used as mood stabilisers?

A

Carbamazepine, Valproate and Iamotrogine

108
Q

What is the pathway to make noradrenaline?

A

Tyrosine = DOPA = dopamine = Noradrenaline = Adrenaline

109
Q

Where is dopamine synthesised?

A

In vesicles

110
Q

What is rebexitine?

A

A NARI (noradrenaline reuptake inhibitor) - not sufficient to treat depressionby itself

111
Q

Which dopamine receptors are targeted to treat schizophrenia?

A

D2 and D4 (the even ones)

112
Q

What are the four dopamine pathways in the CNS?

A

1) Nigrostatial pathway - fine motor control, lost in parkinsons
2) Mesocortical - pleasure-euphoria-reward system
3) Tuberhypophyseal pathway (prolactin = increased lactation)
4) Medullary chemoreceptor trigger zone = nausea and vomitting

113
Q

Which dopamine pathway is targeted when treating scizophrenia?

A

The mesocortical pathway

114
Q

What is the action of amphetamines?

A

Amphetamines stimulate secretion of DA and NA, inhibit MAO and metabolism of DA and NA, displace DA and NA from vesicles,
cause re-uptake transporters to work in reverse.
Activation of reward pathways, increased motor activity

115
Q

What are trannsgenic mice lacking D1 insensitive to?

A

Cocaine and amphetamines

116
Q

What are the side effects associated with chloropromazine and haloperidol (typical antipsychotics)?

A

Motor disturbances and prolactin secretion

117
Q

What are phenothiazines?

A

Antipsychotic drugs which block the effect of dopamine eg chlorpromazine which is used to treat shcizophrenia

118
Q

Give two examples of newer atypical anti psychotic drugs

A

Sulpiride

Clozapine

119
Q

What is the action of most antipsychotic drugs?

A

They are antagonists for the D2 receptor which is inhibitory

This G protein-coupled receptor inhibits adenylyl cyclase activity

Integrated Physiology and Pharmacology (17 decks)

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