CPTP 3.4 Neuropharmacology 2 (Antipsychotics) Flashcards
When is the onset of schizophrenia?
Adolescence & young adulthood
There is a ‘spectrum of symptoms’ for schizophrenia. What does this divide the symptoms into?
- Positive symptoms
- Negative symptoms
What are the ‘positive’ symptoms of schizophrenia?
- Disorders of thought
- Hallucinations
- Paranoia
What are the ‘negative’ symptoms of schizophrenia?
Catatonic Behaviour
- Blunted emotions
- Social withdrawal
- Apathy
What is the importance of positive and negative symptoms?
They respond differently to different medications.
What brain differences are seen in those with schizophrenia?
- Developmental abnormalities in the limbic system
- Smaller temporal lobes
- Enlarged ventricles
Describe a theory of schizophrenia.
Dopamine theory of Schizophrenia: “Schizophrenia is caused by overactive MESOLIMBIC AND MESOCORTICAL dopamine systemS in the brain”
What are the three main dopamine systems in the brain?
- Nigrostriatal
- Mesolimbic/Mesocortical
- Tuberoinfundibular
Where does the tuberoinfundubular pathway run from and to? What does dopamine do at the destination?
Hypothalamus –> pituitary stalk Dopamine acts tonically as prolactin release inhibiting factor (PRIF)
Outline prolactin regulation
Stimulating:
- Suckling
- Hypothalamic nuclei release prolactin releasing factor (PRF)
- PRF Stimulates anterior pituitary to release prolacin
Inhibiting:
• Dopamine from tuberoinfundibular tract inhibits anterior pituitary prolactin release
What does prolactin do?
Stimulates milk production and differentiation of mammary tissue
Where is prolactin released from?
Anterior pituitary
What is released from the posterior pituitary?
Oxytocin
Vasopressin
Where does the nigrostriatal pathway run from and to? What does dopamine do at the destination?
substantia nigra –> dorsal striatum Involved in the initiation and control of movement (extrapyramidal pathway of movement)
What are the diseases of the nigrostriatal pathway?
- Parkinson’s disease
- Huntington’s chorea
What is the relevance of the nigrostriatal pathway with schizophrenia?
No direct relationship, but the drugs used to treat schizophrenia have side effects which affect this pathway
Where does the mesolimbic pathway run from and to? What does dopamine do at the destination?
Ventral tegmentum –> Ventral striatum & hippocampus Reward, addiction, sensory processing
Where does the mesocortical pathway run from and to? What does dopamine do at the destination?
Ventral tegmentum –> frontal cortex Cognition, mood
What causes dopamine imbalance in schizophrenia?
Increased synthesis of dopamine
How do antipsychotic drugs work?
They block D2 receptors in limbic and cortical areas
What were the first antipsychotic drug classes to be high-affinity D2 receptor antagonists? What are the side effects of this and why?
Phenothiazines and thioxanthenes Have tri-cyclic structures (like TCAs but arent) which means its not selective, and has affinity for many receptors:
H1:
- Weight gain
- Sedation
M1:
- Dry mouth
- Blurred vision
- Constipation
- Urinary retention
a1:
• Postural hypotension
D2 (nigrostriatal):
• Extrapyrimidal side effects
D2 (tuberoinfundibular)
- Galactorrhoea
- Gynaecomastea
NB: D2 for mesocortical and mesolimbic pathways is the therapeutic target
Antipsychotics which are specific to D2 receptors may still cause side effects. What are these? Why does this occur?
D2 (nigrostriatal):
• Extrapyrimidal side effects
D2 (tuberoinfundibular):
- Galactorrhoea
- Gynaecomastia
What does ‘tardive’ mean in tardive dyskinesia?
Tardive, because it begins 6 months after initiation of treatment
Is tardive dyskinesia permanent?
Yes
What are the extrapyramidal side effects?
- Parkinson’s symptoms (rigidity, tremor, etc)
- Tardive dyskinesia (repetitive involuntary movement)
What are the side effect profiles of phenothiazines and thioxanthenes?
Group I: Sedation (H1)
Group II: Anticholinergic (M1)
Group III: Extrapyrimidal (D2)
What drug class ditched the tricyclic structure, and were more selective for just D2 receptors? Give an example.
Butyrophenones
• Haloperidol
What are the side effects of butyrophenones?
Extrapyramidal side effects remain
Prolactin side effect remain (galactorrhea and gynaecomastia)
Summarise the 1st generation antipsychotic classes and an example of each
Tricyclic compounds:
- Phenothiazines
- Thioxanthenes
Selective:
• Butyrophenones
What are 2nd generation antipsychotics also known as?
Atypical antipsychotics
Name the 2nd generation antipsychotics. What are the benefits of these?
- Clozapine
- Olanzapine
- Risperidone
- Amisulpiride
- Aripiprazole
- Quetiapine
They have a better EPS profile, and do not have any affinity for M1, a1 or H1
What is the main side effect of:
1) Clozapine?
2) Olanzapine?
3) Risperidone?
Clozapine = agranulocytosis
Olanzapine and risperidone = weight gain and insulin resistant diabetes
Which drugs are good at treating positive and negative symptoms?
Treating positive symptoms –> 1st generation antipsychotics
Treating negative symptoms –> 2nd generation antipsychotics
What are the affinities of 2nd generation antipsychotics?
D2: low
D3: High
D4: High
5-HT2A: High
Recall the D1-like family
D1 & D5
How do atypical (2nd generation) antipsychotics reduce their EPS side effects, while still maintaining therapeutic efficacy?
They have loose binding for D2 receptors, because their dissociation rate is much higher.
In the nigrostriatal pathway, dopamine is released PHASICALLY (lots released infrequently).
Here, the phasic dopamine is enough to displace the drug. (therefore less ‘distortion’ of dopamine signalling here)
However, in the cortex, from the mesocortical pathway (the target), the release of dopamine is tonic (constant, lower levels), therefore the drug is not displaced as much, and can have its antagonistic effect.
There is also a role in the 5-HT2A antagonism having antidepressant effects
What are 1st generation antipsychotics also known as?
Classical, typical
What are the practical distinctions between typical and atypical antpsychotic use?
Atypical have:
- Fewer extrapyrimidal side effects
- More efficacy in treating drug-resistant patients
- Better at treating negative symptoms
