CPTP3.4: Pharmacology of antipsychotics

Question 1

Explain the dopamine theory of schizophrenia.

Answer 1

Schizophrenia is caused by an overactive dopamine system in the brain.

Question 2

There are three main dopamine pathways. Describe the tuberoinfundibular dopamine pathway.

Answer 2

Dopamine travels from the hypothalamus to the pituitary stalk and acts on anterior pituitary gland as prolactin release inhibiting factor (PRIF) and tonically inhibits prolactin.

Question 3

There are three main dopamine pathways. Describe the nigrostriatal dopamine pathway.

Answer 3

Dopamine travels from the substantia nigra to dorsal striatum (part of the extra-pyramidal motor system - initiation and control of movement).

Question 4

There are three main dopamine pathways. Describe the mesolimbic/mesocortical dopamine pathway.

Answer 4

This is mainly dysfunctional in schizophrenia.

Dopamine travels from the ventral tegmental area to (1) ventral striatum and hippocampus (reward, addiction and sensory processing) and (2) frontal cortex (cognition mood/emotions).

Question 5

What is the mechanism of action of antipsychotics? What other receptors do they affinity for?

Answer 5

They block D2 receptors in limbic/cortical areas - D2 antagonists and and have affinity for muscarinic, histamine and adrenergic receptors.

Question 6

What are the major side effects of antipsychotics due to their lack of selectivity for D2 receptors?

Answer 6

Histamine (H1) receptor: sedation / weight gain

Muscarinic (M1) receptor: dry mouth / blurred vision / constipation / urinary retention

Adrenergic (alpha-1) receptor: postural hypotension (inhibition of alpha receptors inhibit vasoconstriction normally initiated by baroreceptor reflex).

Question 7

What are the major side effects of antipsychotics due to their affinity for D2 receptors?

Answer 7

(1) Nigrostriatal pathway: EPS side effects
a. Parkinson’s syndrome: tremor, muscle rigidity, loss of facial expression
b. Tardive dyskinesia (permanent): lip smacking, chewing, rocking, rotation of the ankles or legs, marching in place and repetitive sounds [humming/grunting]
(2) Tuberoinfundibular: prolactin secretion -> galactorrhoea / gynaecomastea [due to loss of tonic prolactin inhibition]

Question 8

What are the classifications of 1st generation antipsychotics? Describe them.

Answer 8

1. Phenotiazine:

a. Chlorpromazine (group 1: H1 receptor side effects)
b. Thioridazine (group 2: M1 receptor side effects)
c. Fluphenazine (group 3: EPS)

2. Thioxanthenes:

Flupenthixol - similar profile to phenotiazines

3. Butyrophenones:

Haloperiodol (lack M1 and H1 activity but has EPS)

Question 9

Describe 2nd generation antipsychotics (atypical antipsychotics).

Answer 9

Do not have tricyclic structures

Lower % of EPS side effects

Question 10

What are some 2nd generation antipsychotics? Describe them.

Answer 10

Clozapine/olanzapine/risperidone/amisulpride/quetiapine:

better EPS side effect profile without loss of antipsychotic efficacy

clozapine associated with agranulocytosis (increased vulnerability to infectino)

olanzapine/risperidone: high incidence of weight gain and metabolic syndrome (insulin resistance -> resultant diabetes/hyperglycaemia) -> compliance issue

2ND GENERATION ANTIPSYCHOTICS ARE BETTER AT TREATING NEGATIVE SYMPTOMS

lower affinity for D2 receptor and higher affinity for D3/D4 receptor

Question 11

Describe the hypothesis for the mechanism of action of atypical (2nd gen) antipsychotics

Answer 11

Atypicals do have affinity for D2 receptors (EPS symptoms) but they have a faster dissociation rate from D2 receptors -> can then be displaced by physiological phasic bursts of dopamine transmission in dopamine nigrostriatal pathways -> less incidence of EPS