【Pharmacology】Antipsychotics

Antipsychotics

treat psychotic disorders such as schizophrenia mania due to bipolar disorder and severe depression

Content:

1. Role of dopamine
2. Dopamine receptors
3. Antipsychotics
a. First generation agents --- typical
b. Second-generation agents --- atypicals
4. Reference

1. Role of dopamine

Monoamine neurotransmitter dopamine plays a key role in the dopamine hypothesis, which argues that the unusual behavior and experiences associated with psychosis can be largely explained by changes in dopamine function in the brain.

Four major pathways by which it affects the brain

a. Mesolimbic pathway

thought to be hyperactive in schizophrenia
to mediate positive symptoms of psychosis such as delusions and hallucinations

b. Mesocortical pathway

thought to be under active in schizophrenia
mediate negative psychotic symptoms such as loss of motivation and social withdrawal

c. Nigrostriatal pathway

part of the extrapyramidal nervous system
controls motor function and movement deficiency of dopamine

lead to dystonia and parkinsonian symptoms

excess of dopamine can lead to hyperkinetic movements

eg, tics and dyskinesias

d. Tuberoinfundibular pathway

controls prolactin secretion specifically dopamine

inhibits prolactin release

prolactin is a hormone that enables milk production and is also involved in the control of sexual desire and regulation of immune system

Four major pathways by which it affects the brain

2. Dopamine receptors

Five primary types: D1, D2, D3, D4 and D5

D1 and D2 receptors are found in the highest density in nearly all of the pathways involved in psychotic disorders
D2 receptors are the most clinically relevant

main targets of antipsychotic drugs

3. Antipsychotics

can be grouped into

older first generation agents --- typical
newer second-generation agents --- atypicals

a. First generation agents --- typical

block D2 receptors
not selective for any of the four dopamine pathways

Thus will block D2 receptors in almost all areas of the brain

has positive as well as negative consequences

👍blockade of dopamine receptors in the mesolimbic pathway

reduces positive symptoms such as delusions and hallucinations

👎blockade of dopamine receptors in the mesocortical pathway (underactive in schizophrenia)

worsening of negative symptoms

lead to diminished energy lack of motivation restrictions in emotional and verbal expressiveness and social disengagement

👎blockade of dopamine receptors in the nigrostriatal pathway

lead to extrapyramidal disorders tardive dyskinesia and parkinson's-like symptoms

eg, tremors, muscle rigidity, and difficulty in starting and stopping movements

👎blockade of dopamine receptors in the tuberoinfundibular pathway

cause increase in blood prolactin levels

may lead to galactorrhea gynecomastia and sexual dysfunction

a. First generation agents --- typical blockage pathway

Based on their affinity for D2 receptors, typical antipsychotics are often subclassified as

High potency

Haloperidol
Fluphenazine
Prochlorperazine
Trifluoperazine

Produce stronger antipsychotic effect at relatively low doses

However, they also tend to cause more extrapyramidal side effects and greater increase in prolactin levels

Low potency

Chlorpromazine

Do not bind to D2 receptor as tightly as the high potency agents

Affect a range of other receptors, eg,

blockade of alpha-adrenergic cholinergic: orthostatic hypotension
blockade of muscarinic receptors: anticholinergic symptoms, eg, dry mouth, blurred vision, difficulty urinating and constipation
blockade of H1-histamine receptors: sedation and some weight gain

b. Second-generation agents --- atypicals

primarily block only D2 receptors atypical agents
appear to block both D2 receptors as well as serotonin receptors subtype 2A

because serotonin inhibits dopamine release agents that block serotonin receptors
may increase dopamine levels in brain areas
need it furthermore atypicals occupy D2 receptors transiently and dissociate quickly
allowing for relatively normal dopamine neurotransmission

Modest D2 receptor blockade in combination with serotonin receptor blockade

significantly lower the incidence of extrapyramidal side effects
decrease negative symptoms and improve cognition

Drug:

Aripiprazole
Clozapine
Lurasidone
Olanzapine
Quetiapine
Risperidone
Ziprasidone

Dopamine and serotonin 2A receptor blockade atypical antipsychotics also bind to many other targets

eg, other subtypes of serotonin receptors, histamine alpha-adrenergic and muscarinic receptors

so, side-effects of second-generation agents can vary

Side-effects of second-generation agents

a. Clozapine and Olanzapine

have strong affinity for serotonin receptors subtype 2C
weight gain
hyperglycemia
dyslipidemia

b. Clozapine, Olanzapine and Quetiapine

have strong affinity for H1 receptors
sedation
weight gain

c. Clozapine and Risperidone

have significant affinity for alpha-1-adrenergic receptors
orthostatic hypotension

d. Risperidone

strongest affinity for D2 receptors
has the highest potential to induce extrapyramidal side effects and hyperprolactinemia

e. Clozapine

the only antipsychotic that can cause serious condition called agranulocytosis
occurs when the bone marrow does not produce enough white blood cells called granulocytes
This condition can be fatal periodic, so blood cell counts must be performed to ensure patient safety

4. Reference

https://youtu.be/nKkIh1B2Js8

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