Antipsychotics (save pharmaco)

Question 1

How does D2 antagonism correlates with clinical efficacy?

Answer 1

o The higher the D2 receptor Kd, the lower the affinity of the receptors, and the less efficacious the drug is (higher the mean clinical dosage).
o D2 receptor Kd against mean clinical dosage (linear graph)
o From most efficacious to least efficacious: fluphenazine -> haloperidol -> trifluoroperazine -> clozapine -> chlorpromazine

Question 2

Molecular (receptor sensitivity) basis of antipsychotic side effects:

1. Chlorpromazine
2. Haloperidol

Answer 2

1. Chlorpromazine
   - M1: dry mouth, blurred vision, constipation
   - H1: sedation, weight gain
   - α_1: postural hypotension, dizziness
   - D2
2. Haloperidol
   - Has far less side effects than chlorpromazine (only has α_1and D2 side effects)

Question 3

Names of typical and atypical antipsychotics

Answer 3

Typical:

• chlorpromazine (first antipsychotic drug)
• haloperidol (most commonly used)

Atypical:

• clozapine
• risperidone
• amisulpride

Question 4

Receptor affinities of antipsychotics

Answer 4

• Haloperidol binds to pretty much everything except H1.
• Amisulpride is a selective D2/D3 antagonist but is lately reported to have 5-HT7 antagonism as well.
• Clozapine and olanzapine bind to pretty much everything
• Risperidone bind to everything except D1

Question 5

Atypical antipsychotics produce less extrapyramidal side effects (EPS) than typical antipsychotics

Answer 5

• Acute dystonia (cogwheel rigidity and tremor at rest)
• Tardive dyskinesia and akathisia (repetitive and stereotyped involuntary movements of face, tongue and limbs)
• Serotonin-dopamine antagonism is at the core of most antipsychotics

Question 6

Clozapine

Answer 6

• Has the full M1. H1 and α_1 side effects
• Can cause agranulocytosis
• Olanzapine is made to circumvent the issue of agranulocytosis.

Question 7

Risperidone

Answer 7

Has more of the α_1 side effects  postural hypotension and tachycardia

Question 8

Amisulpride

Answer 8

• Largely on mammary glands and tissues
• Increased prolactin secretion
• Breast swelling, pain and lactation
• Gynaecomastia in males

Question 9

Aripiprazole

Answer 9

• Partial agonist
• Atypical antipsychotic (has the 5-HT/D2 antagonism)
• Less efficacious than dopamine but more efficacious than haloperidol

Question 10

Drug-induced diabetes

Answer 10

• Effect is strong for clozapine, olanzapine and risperidone
• Amisulpride is an exception
• Effects can be reversed

Question 11

Drug-induced weight gain

Answer 11

• Effect is strong for clozapine, olanzapine and risperidone

Question 12

Why do atypical antipsychotics produce less EPS?

Answer 12

- Potent 5-HT2A antagonism vs weak D2 antagonism -> lower EPS and higher efficacy against negative symptoms 
> Clozapine, olanzapine
- High D3 to D2 antagonism: 
> Amisulpride 
- High D4 to D2 antagonism: 
>Clozapine 
- High D2 to D1 receptor antagonism: 
>Amisulpride, risperidone

Question 13

Additional benefits of antipsychotics include:

Answer 13

o Clozapine, risperidone

• More effective in combating negative symptoms
• In ameliorating cognitive dysfunction
• In mood stabilization than typical antipsychotics