3.4 Antipsychotics

Question 1

What are the positive symptoms of schizophrenic?

Answer 1

Disorders of thought/disorganised behaviour Hallucinations aural or visual Paranoia

Question 2

What are the negative symptoms of a schizophrenic?

Answer 2

Blunted emotions and anhedonia Social withdraw Apathy/loss of energy

Question 3

What causes schizophrenia?

Answer 3

‘Schizophrenia is caused by an overactive dopamine system in the brain’

Question 4

What is the tuberoinfundibular dopamine pathway?

Answer 4

Hypothalamus - pituitary stalk Anterior pituitary - dopamine acts as a prolactin release inhibiting factor - tonic inhibition of lactation

Question 5

What is the nigrostriatal pathway?

Answer 5

Substantia nigra to the dorsal striatum

Question 6

What is the dorsal striatum?

Answer 6

• Part of extra-pyramidal motor system
• involve din initiation and control of movement
• disease of this system - Parkinsons and Huntingdons

Question 7

What is the mesolimbic/mesocortical pathway?

Answer 7

Ventral tegmental area

1. Ventral striatum and hippocampus - reward, addiction and sensory processing
2. Frontal cortex - cognition and mood

Question 8

Which dopamine pathwayis mainly affected by schizophrenia?

Answer 8

mesolimbic/mesocortical DA

Question 9

What evidence is there for what causes schizophrenia?

Answer 9

Amphetamine causes schizophrenic like symptoms

Dopamine receptor antagonists reduce schizophrenic symptoms

Affinity for dopamine receptors correlates with therapeutic efficacy

Question 10

What do antipsychotics do?

Answer 10

Affinity of antipsychotics for dopamine D2 receptors in particular correlates with therapeutic efficacy

Antipsychotic drugs block D2 receptors in limbic/cortical areas

Antipsychotics developed were high affinity D2 receptor antagonists

Three ringed/tricyclic structure

Affinity for other (non dopamine receptor) subtypes

Muscarinic, Histamine, Adrenergic receptors

Question 11

What side effects do anti-psychotics have?

Answer 11

• H1 mediated
  
  • Sedation, weight gain
• M1 mediated
  
  • Dry mouth blurred, vision, constipation, urinary retention
• α1 mediated
  
  • Postural hypotension

Question 12

What effect do anti-psychotics have on nigrostriatal pathway?

Answer 12

Parkinson’s syndrome

• Tremor
• Muscle rigidity
• Loss of facial expression

Tardive Dyskenisia

• Repetitive rhythmical involuntary movements,
• lip smacking, chewing,
• rocking, rotation of the ankles or legs,
• marching in place, and
• repetitive sounds such as humming or grunting
• Don’t return to normaal after stopping the drug

Question 13

How do anti-psychotics affect the Tuberoinfundibular pathway?

Answer 13

Galactorrhoea

Gynacomastea

Question 14

How were anti-psychotics initially classified?

Answer 14

On the basis of thei side effects

Phenothiazines

• Group I Sedation Chlorpromazine
• Group II Anticholinergic Thioridazine
• Group III EPS Fluphenazine

Question 15

Why does haloperidrol have less side effects?

Answer 15

(Butyrophenones) Lack muscarinic and antihistamine activity (no sedation) but it does have an EPS a problem

Question 16

What led to the generation of 2nd generation of atypical anti-psychotics?

Answer 16

High incidence of side effects

Question 17

What are the 2nd generation atypical anti-psychotics?

Answer 17

Clozapine, Olanzapine, risperidone, amisulpiride, quetiapine

Question 18

What are the side effects of the 2nd generation antipsychotics?

Answer 18

• -Better EPS side effect profile (without loss of antipsychotic efficacy)
• -But clozapine associated with agranulocytosis
• -High incidence of weight gain and metabolic syndrome,
  
  • -Risperidone, olanzapine
    
    • -Weight gain + Insulin resistance and resultant diabetes/hyperglycaemia
• • better at treating negative symptoms
• -Lower affinity for D2 receptor!
• -High affinity for D3, D4 receptors (D2 family) and 5‑ HT2A receptor

Question 19

What is the Hypothesis for mechanism of action atypical antipsychotics?

Answer 19

• Atypicals do have affinity for D2 receptor, however they have a much faster dissociation rate from the D2 receptor (Koff) (loose binding)
• These drugs can be displaced by physiological phasic bursts of DA transmission (important in DA striatal pathways)
• Results in less distortion of physiological DA signalling in striatal pathways
• Cannot exclude the role of 5-HT2

Question 20

What are the 2 main categories of anti-psychotics?

Answer 20

•Classical/typical

Chlorpromazine, flupenthixol, haloperidol

•Atypical

Clozapine, sulpiride, olanzapine, risperidone

Question 21

What is the distinction between typical and atypical based on?

Answer 21

• Incidence of extrapyramidal side effects
• Efficacy in treating treatment resistant patients
• Efficacy against negative symptoms