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Pharm > Lecture 12: Drugs used to treat Psychosis > Flashcards

Lecture 12: Drugs used to treat Psychosis Flashcards

1
Q

What does Psychotic disorders mean?

A

The term used to describe a range of mental disorders that involve symptoms of psychosis

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2
Q

What is Psychosis?

A

The mental disorders in which there is a loss of contact with reality, affecting a person’s ability to think, feel and act

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3
Q

What are the three types of symptoms of Schizophrenia?

A
  • Positive
  • Negative
  • Cognitive
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4
Q

When is Schizophrenia diagnosed?

A

When a person has two or more symptoms for more than six months

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5
Q

What are the positive symptoms of schizophrenia?

A

Mental phenomena that are absent in healthy individuals
•Hallucination
•Delusions

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6
Q

What are the Negative symptoms of schizophrenia?

A

Loss or impairment of normal psychological functions
•Loss of social motivation
•Social withdrawal

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7
Q

What are the Cognitive symptoms of schizophrenia?

A
  • Poor concentration
  • Disorganized thinking
  • Poor memory
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8
Q

What is the risk of Schizophrenia highly influenced by?

A

Genes

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9
Q

When does Schizophrenia often manifest?

A

In early adulthood

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10
Q

What neurotransmitters are thought to be associated with Schizophrenia?

A
  • Dopamine
  • Glutamate
  • GABA
  • Serotonin
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11
Q

What is meant with the statement Schizophrenia is a biochemical Disorder?

A

People with schizophrenia have altered levels of neurotransmitters

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12
Q

What are the three Biochemical Theories of Schizophrenia?

A
  • Dopamine hypothesis
  • Glutamate hypothesis
  • Serotonin (5-HT) hypothesis
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13
Q

What is the overarching theme to the Dopamine Hypothesis?

A

Symptoms of schizophrenia are due to the hyperactivity of the dopamine system

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14
Q

What is the inferential evidence that support the Dopamine Hypothesis?

A
  • Drugs that increase synaptic dopamine can cause delusions and hallucinations at high doses
  • Drugs that block dopamine receptors are effective antipsychotics
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15
Q

Where are Dopamine neurons located?

A

In a few discrete regions of the brain

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16
Q

Where is the largest population of dopamine neurons located?

A

In the midbrain (ventral tegmental area and substantia nigra)

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17
Q

What is the Mesocortical/Mesolimbic system?

A

Dopamine neurons located in the ventral tegmental area thar project to the striatum and prefrontal cortex

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18
Q

What is the function of the Mesocortical/Mesolimbic system?

A

Mediate memory, learning, affect and thought organization

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19
Q

What does hyperactivity in the Mesocortical/Mesolimbic pathway contribute to?

A

Psychotic symptoms

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20
Q

What is blocking dopamine transmission in the Mesocortical/Mesolimbic pathway effective at?

A

Treating positive symptoms of schizophrenia

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21
Q

What does the Mesocortical/Mesolimbic system start with?

A

Dopamine neurons in the ventral tegmental area

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22
Q

What are dopamine neurons in the striatum important for?

A

Reward in behavior associated with drugs like cocaine

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23
Q

What are dopamine neurons in the cortex important for?

A

Memory, learning and organization

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24
Q

What does hyperactivity in the Ventral tegmental cortical tract do?

A

Drives the psychosis associated with schizophrenia

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25
Q

What kind of receptors are Dopamine receptors?

A

G-protein coupled receptors

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26
Q

What are the two types of Dopamine receptors?

A 
D1 receptors (Gs)
D2 receptors (Gi)
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27
Q

What G coupled receptor is D1 coupled to?

A

Gs

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28
Q

What G coupled receptor is D2 coupled to?

A

Gi

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29
Q

What do D1 Gs coupled receptors do?

A

Stimulate AC and activate cAMP dependant kinases

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30
Q

What do D2 Gi coupled receptors do?

A

Inhibit the activity of adenylate cyclase

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31
Q

The blocking of which Dopamine receptors is directly related to clinical antipsychotic potency?

A

D2 receptors

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32
Q

Which Dopamine receptors are blocked with anti-psychotics?

A

D2 receptors

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33
Q

What does antipsychotics blocking the activity of D2 do?

A

Stops D2 from inhibiting AC

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34
Q

What are the other Dopamine Pathways are not associated with psychosis?

A
  • Nigrostriatal system

* Tuberoinfundibular system

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35
Q

What is the Nigrostriatal system?

A

Dopamine neurons in the substantia nigra that project to the striatum

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36
Q

What is the Nigrostriatal system involved in?

A

Movement initiation

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37
Q

What is inhibiting Nigrostriatal system associated with?

A

Tardive Dyskinesias

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38
Q

What is Tardive Dyskinesias?

A

Involuntary movements of the face and body after long-term use of some antipsychotics that inhibit dopamine transmission

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39
Q

Which neurons degenerate in parkinson’s disease?

A

The Nigrostriatal neurons

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40
Q

What is the Tuberoinfundibular system?

A

Dopamine neurons in the arcuate nucleus that control hormone release in the pituitary

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41
Q

What does Dopamine released in the Tuberoinfundibular System do?

A

Inhibits the secretion of prolactin and growth hormone

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42
Q

What is Hyperprolactinemia?

A

The long-term use of some antipsychotics that affect the dopamine pathways of the tuberoinfundibular system

43
Q

Other than hyperprolactinemia, what does inhibiting the Dopamine in the Tuberoinfundibular pathway associated with?

A

Amenorrhea, decreased libido, infertility

44
Q

What is the overall Glutamate hypothesis?

A

Symptoms of schizophrenia linked to deficiencies in glutamate signalling, particularly in the cortex

45
Q

What is the support of the Glutamate Hypothesis for psychosis?

A

Phencyclidine (PCP/Angel dust) and Ketamine which are NMDA antagonists produce hallucination and paranoid delusions

46
Q

What is the current theory of Glutamate and schizophrenia and NMDA receptors?

A

Schizophrenia is associated with hypofunctional NMDA receptors on GABA interneurons in the cerebral cortex

47
Q

What does the hypofunction of GABA interneurons in the cerebral cortex cause?

A

This hypofunction leads to overactivation of downstream glutamate signalling to the VTA

48
Q

What are Dopamine neurons under the control of?

A

Glutamate neurons that lie in the cortex that project to the VTA

49
Q

What are Glutamate neurons under the control of?

A

GABA interneurons

50
Q

What have scientists found in the brains of Schizophrenics in terms of glutamate receptors?

A

They have a hypofunctional glutamate receptor on the GABAergic interneurons

51
Q

What does the NMDA receptor do?

A

Binds to glutamate and causes the NMDA channel to open and a flow a positively charged ions leads to depolarization of GABAergic neurons

52
Q

What should depolarization of GABAergic neurons do?

A

Release GABA to bind to GABAergic receptors on the glutamate neuron

53
Q

What kind of receptors are GABA receptors?

A

They are inhibitory

54
Q

What does GABA binding to GABA receptors on Glutamate neurons do?

A

Shuts off the Glutamate neuron

55
Q

What neurons activate dopamine neurons?

A

Glutamate neurons

56
Q

What does shutting off the Glutamate neurons by GABA do?

A

Reduces the activity of dopamine release because glutamate usually activates Dopamine neurons

57
Q

What do GABAergic neurons in the cortex do?

A

Inhibit dopamine neurons by inhibiting Glutamate neurons which activate dopamine neurons

58
Q

What is wrong with the NMDA receptors on GABA neurons that glutamate is supposed to bind to and activate GABA neurons in order to inhibit glutamate neurons in people with Schizophrenia?

A

They don’t work very well

59
Q

What is a consequence of the NMDA receptors not working?

A

Glutamate released on the GABAergic neurons are no longer able to to activate GABA neurons and as a consequence GABA neurons can’t release GABA in order to inhibit the Glutamine neurons. This causes glutamate to release onto Dopamine receptors and activate dopamine and create a hyperactivity of dopamine which causes psychosis

60
Q

What overall does the Serotonin Hypothesis state?

A

That the symptoms of schizophrenia are due to increased serotonin signaling

61
Q

What is the inferential evidence of the serotonin hypothesis?

A

5HT agonists are hallucinogenic. 5HT antagonists improve positive symptoms of schizophrenia

62
Q

How is it hypothesized in the serotonin hypothesis that serotonin causes hallucinations?

A

5HT-2A receptors in the prefrontal cortex cause hallucinations by enhancing excitation of glutamate neurons which activate the mesolimbic dopamine system

63
Q

What do 5HT-2A antagonists do?

A

Block glutamate release in the cortex, thus reducing hallucination and other positive symptoms

64
Q

What is the difference between the Serotonin and Glutamate hypothesis?

A

The serotonin hypothesis states that the upstream control of glutamate neurons is serotonin and not hypofunction of the NMDA receptor GABA interneurons

65
Q

What are the two major groups of antipsychotic drugs?

A
  • First gen antipsychotics/Typical antipsychotics

* Second gen antipsychotics/Atypical antipsychotics

66
Q

What do First gen antipsychotics target?

A

Both classes of dopamine receptors (D1 and D2)

67
Q

What does the efficacy of First gen antipsychotics relate to?

A

D2 receptor antagonism

68
Q

What are the two first gen antipsychotics?

A

Haloperidol and chlorpromazine

69
Q

What kind of drugs are second gen antipsychotics?

A

Antagonists

70
Q

What receptors do second gen antipsychotics target?

A

They are antagonists at 5HT and D2 receptors

71
Q

Why do second gen antipsychotics have less dopamine related side effects than first gen antipsychotics?

A

Because they bind with lower affinity to dopamine receptors

72
Q

What are the second gen antipsychotics?

A

Clozapine and Risperidone

73
Q

What dopamine relate side effects do second gen antipsychotics lack?

A

Tardive Dyskinesia and prolactin release

74
Q

How much occupation of D2 receptors is required to produce an antipsychotic effect of typical and atypical antipsychotics?

A

60-80%

75
Q

What does 80% D2 occupancy of antipsychotics do?

A

Results in side effects such as
•Parkinson-like side effects (extrapyramidal symptoms)
•Elevated prolactin (hyperprolactinemia) and
•Tardive dyskinesia

76
Q

What is the Therapeutic window of the typical antipsychotics?

A

It has a very narrow therapeutic window

77
Q

Why do Atypical antipsychotics have a wider therapeutic window?

A

Because they have a lower binding affinity to D2 receptors

78
Q

What can the relationship between how well a drug binds and how well a drug dissociates to a ligand be expressed by?

A

The ratio of the association constant and the ratio of the dissociation constant aka the equilibrium constant (kd)

79
Q

What does a Low Koff and a high Kon have in terms of the Kd and affinity?

A

This will cause a low Kd and a high affinity

80
Q

How does Dopamine work in the mesolimbic-nigrostriatal pathway?

A

Dopamine is released into the synaptic cleft where it binds to receptors on the postsynaptic membrane

81
Q

What are the characteristics of Dopamine binding in the mesolimbic/nigrostriatal pathway?

A

It is a tight squeeze and there is a high degree of receptor rebinding

82
Q

How does Dopamine work in the Tuberoinfundibular pathway?

A

Dopamine is secreted into the bloodstream and carried across the BBB to the pituitary gland

83
Q

What are the characteristics of Dopamine binding in the Tuberoinfundibular pathway?

A

There is a high degree of clearance and less receptor rebinding

84
Q

What generation antipsychotic is Haliperidol?

A

A first generation

85
Q

What are the characteristics of Haloperidol at the D2 receptor?

A

It binds very well to the D2 receptor and tends not to let go

86
Q

What would the Kd of Haloperidol be?

A

It would have a high dissociation constant because it tends not to dissociate (Kon>Koff)

87
Q

What are the effects of Haloperidol at the VTA/Substantia Nigra/Striatum versus the pituitary?

A

At the Striatum it will have a high rate of receptor binding potential and in the pituitary it will also have a high rate of receptor binding

88
Q

Why does Haloperidol (first gen) have high extrapyramidal side effects?

A

Because it has high binding in the Striatum and in the Pituitary

89
Q

What generation antipsychotic is Chlorpromazine?

A

First gen

90
Q

What is the affinity for the receptor in Chlorpromazine?

A

It has high binding affinity for the receptor

91
Q

What is the difference between Haloperidol and Chlorpromazine at the receptor?

A

Chlorpromazine and Haloperidol both bind quickly but Chlorpromazine unbinds a lot easier

91
Q

What is the difference between Haloperidol and Chlorpromazine at the receptor?

A

Chlorpromazine and Haloperidol both bind quickly but Chlorpromazine unbinds a lot easier

92
Q

What are the effects of Chlorpromazine at the VTA/Substantia Nigra/Striatum versus the pituitary?

A

Because Chlorpromazine unbinds very quickly in the striatum the tight space helps it to rebind better but in the pituitary blood flow doesn’t allow it to rebind

93
Q

What are the side effects of Chlorpromazine?

A

Because it still binds in the striatum it will still have high extrapyramidal effects but because it does not bind highly in the pituitary it doesn’t really effect prolactin release

94
Q

What kind of Antipsychotic is Clozapine?

A

A second gen antipsychotic

95
Q

What is the kinetic profile of Clozapine?

A

It has a slow on and a fast off meaning that it is really slow to bind to the receptor and unbinds quickly. So it is less likely to occupy the receptors

96
Q

What are the effects of Clozapine at the VTA/Substantia Nigra/Striatum versus the pituitary?

A

In the striatum even though it is a tight synaptic space the fact that it’s not binding well in the first place means its less likely to occupy the receptors. And in the pituitary it is cleared in the pituitary quicker

97
Q

What are the Side effects of Clozapine?

A

It tends to have lower extrapyramidal effects and less effects on prolactin release

98
Q

Aside from their side effects in the striatum and pituitary what effects can antipsychotics have?

A

They can have affinity for other receptors like serotonin, adrenergic, GABA and glutamate receptors

99
Q

What other receptor does Clozapine have an affinity for?

A

D4 receptors

100
Q

What are the effects of Clozapine binding to D4 receptors?

A

Agranulocytosis (loss of WBCs) making an individual more susceptible to infection

101
Q

Why is Clozapine not a first choice antipsychotics?

A

Because it binds to WBCs and makes an individual more susceptible to infection and death

102
Q

What are the side effects of second gen antipsychotics?

A
  • Cardiovascular effects
  • Metabolic syndrome
  • Diabetes
  • Weight gain

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