Antipsychotics

Question 1

What is the principal mechanism of action of antipsychotics?

What are they principally used for?

Answer 1

• Common property of antagonising the actions of dopamine in the brain.
• Mainly used in the treatment of schizophrenia and other psychotic illnesses.

Question 2

What are the clinical features of schizophrenia?

Answer 2

• Positive symptoms:
  
  • ​Delusions
  • Hallucinations
  • Thought disorders
• Negative symptoms:
  
  • ​Withdrawl from social contact and flattening of emotional responses.

Question 3

Describe the dopamine theory.

Answer 3

• Amphetamine produces symptoms almost indistinguishable from schizophrenia.
• D2-receptor agonists produce similar symptoms in animals and exacerbate symptoms in humans.
• Strong correlation between clinical potency ofantipsychotics and D2 blocking action.
• ↑ dopamine content in restricted area of the temporal lobe of schizophrenics (amygdala).
• ↑ dopamine synthesis and release in the striatum of schizophrenics.

Question 4

Describe the glutamate theory.

Answer 4

• NMDA receptor antagonists (e.g. phencyclidine andketamine) produce psychotic symptoms.
• ↓ glutamate and receptor density reported in post- mortem schizophrenic brains.
• Transgenic mice with ↓ NMDA receptor expression show stereotypic schizophrenic behaviours and ↓ social interactions.
  
  • respond to antipsychotics.
• Glutamate and dopamine exert excitatory and inhibitory effects respectively on GABAergic striatal neurones which project to the thalamus and constitute a sensory ‘gate’.
• Too little glutamate or too much dopamine disables the ‘gate’ allowing uninhibited sensory input to reach the cortex.
• Excess dopamine could be responsible for the positive symptoms and reduced glutamate for the negative symptoms.

Question 5

What are the categories of first generation (classical) antipsychotics?

Give an example of each.

Answer 5

• Phenothiazines
  
  • chlorpromazine
  • fluphenazine
  • pipotiazine
• Butyrophenones
  
  • haloperidol
• Thioxanthines
  
  • flupentixol
  • zuclopenthixol

Question 6

What are the categories of second generation (atypical) antipsychotics?

Give an example of each.

Answer 6

• Benzamides
  
  • Amisulpride (selective D2 and D3 receptor antagonists).
• Dibenzodiazepines
  
  • Clozapine and Olanzapine (very unselective receptor blocking profile).
• Others
  
  • Risperidone, paliperidone (mixture of receptor types blocked)
  • Quetiapine (α adrenoceptor blocker)
  • Aripiprazole (Dopamine and 5-HT antagonist)

Question 7

Describe the action of second generation antipsychotics.

Answer 7

• Overcome some of the problems of the classical

neuroleptics.

• Show efficacy in treatment-resistant patients.
• Improve the negative as well as positive symptoms.
• No real evidence that they are more effective than the first generation classical neuroleptics in controlling symptoms.

Question 8

How is the distinction between typical and atypical groups defined?

Answer 8

• Not clearly defined, but rests on:
  
  • Receptor profile
  • Incidence of extrapyramidal side-effects
    
    • Less in atypical group
  • Efficacy in treatment-resistant group of patients
  • Efficacy against negative symptoms

Question 9

Look at the relatice receptor affinity of antipsychotic drugs (don’t memorise).

Answer 9

• α₁ receptors - most associated with blood vessels
• H₁ receptors - histamine
• mACH receptors - muscarinic ACh
• 5-HT_2A - serotonin.

Question 10

What are the behavioural effects of antipsychotics?

Answer 10

• Apathy and reduced initiative
• Display few emotions, drowsy
  
  • Can be easily stirred from this
• Aggressive tendencies inhibited
• Effects are distinct from those produced by hypnotics and anxiolytics

Question 11

What are the main types of motor disturbances caused by antipsychotics?

Answer 11

• Acute, reversible Parkinson-like symptoms
  
  • due to block of nigro-striatal dopamine receptors
• Slowly developing tardive dyskinesia
  
  • one of the most serious problems with antipsychotics

Question 12

Describe tardive dyskinesia.

Answer 12

• Involuntary movements of face and limbs
• Appears after months/years of treatment
• Associated with proliferation of dopamine receptors in the corpus striatum
• Treatment is generally unsuccessful
• Less common with newer antipsychotics

Question 13

What are the other unwanted effects of antipsychotics?

Answer 13

• Endocrine actions
  
  • ↑ prolac􏰀tin secreti􏰀on by blocking D2 receptors in the pituitary.
• Anti-muscarinic actions
  
  • Blurring of vision, dry mouth & eyes, constipation.
  • Can help attenuate extrapyramidal actions.
• α-adrenoreceptor blocking actions
  
  • Orthostatic hypotension.
• H₁-receptor blocking actions
  
  • Sedative and anti-emetic actions.

Question 14

Give a summary of the unwanted effects of antipsychotics.

Answer 14

• Postural hypotension
• Sedation
• Weight gain
• Endocrine actions
• Diabetes

Autonomic actions (atropine-like)

• Extrapyramidal actions
• Jaundice
• Leucopoenia and agranulocytosis
• Skin reactions (itchy rash)
• Neuroleptic malignant syndrome

Question 15

Look at the relative adverse effects of antipsychotics (do not memorise).

Answer 15

Question 16

Describe the variability in uptake of antipsychotic drugs.

Answer 16

• Very different uptake between individuals - pharmacokinetics is different in each different patient.

Question 17

Describe the treatment algorithm for first-episode schizophrenia.

Answer 17

Question 18

What are the different clinical uses of antipsychotic drugs?

Answer 18

• Schizophrenia
  
  • Both classical and atypical depending on side effects.
• Acute Behavioural Emergencies and Mania
  
  • Chlorpromazine
  • Haloperidol
• Treatment of emesis
  
  • Prochlorperazine
• Huntington’s disease
  
  • e.g. Olanzapine, Risperidone and Quetiapine
• Occasionally used in depression
  
  • Flupentixol