【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

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

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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