Pharmacology - ANTIPSYCHOTICS (MADE EASY)

Summary

This lecture explores the pharmacology of antipsychotic drugs, focusing on their role in treating conditions like schizophrenia, bipolar disorder, and severe depression. It delves into the dopamine hypothesis of psychosis, explaining the four major dopamine pathways in the brain and how they influence symptoms. The video differentiates between first-generation (typical) and second-generation (atypical) antipsychotics, discussing their mechanisms, effects on dopamine receptors, and associated side effects such as extrapyramidal symptoms, prolactin increase, and metabolic changes. It also highlights notable drugs like Clozapine, Haloperidol, and Risperidone.

Takeaways

• 🧠 Antipsychotics are used to treat psychotic disorders such as schizophrenia, bipolar disorder, and severe depression.
• 🧬 Dopamine plays a central role in the development of psychosis, with changes in dopamine function linked to psychotic behaviors.
• 🔄 There are four major dopamine pathways: mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular, each affecting different brain functions and psychosis symptoms.
• 💊 First-generation (typical) antipsychotics primarily block D2 receptors, reducing positive symptoms but potentially worsening negative symptoms and causing side effects.
• 💥 High-potency typical antipsychotics (e.g., Haloperidol) tend to cause more extrapyramidal side effects, while low-potency agents (e.g., Chlorpromazine) have broader receptor effects, leading to varied side effects.
• 🚨 Blocking dopamine receptors in the nigrostriatal pathway can lead to motor issues like tardive dyskinesia, and in the tuberoinfundibular pathway, it can cause increased prolactin levels.
• 🌐 Second-generation (atypical) antipsychotics block both D2 and serotonin receptors, resulting in fewer extrapyramidal side effects and improved management of negative symptoms and cognition.
• ⚖️ Atypicals also interact with other receptors, and specific agents (e.g., Clozapine, Olanzapine) can cause metabolic issues like weight gain and hyperglycemia.
• 💊 Risperidone has the strongest affinity for D2 receptors among atypicals, increasing its potential for extrapyramidal side effects.
• 🔬 Clozapine can cause agranulocytosis, a serious condition requiring regular blood tests to monitor white blood cell levels.

Q & A

What are antipsychotics primarily used to treat?

Antipsychotics are primarily used to treat psychotic disorders such as schizophrenia, mania due to bipolar disorder, and severe depression.

What is the dopamine hypothesis in relation to psychosis?

The dopamine hypothesis suggests that the unusual behavior and experiences associated with psychosis can largely be explained by changes in dopamine function in the brain.

What are the four major dopamine pathways in the brain, and how do they relate to psychotic symptoms?

The four major dopamine pathways are: 1) Mesolimbic pathway, which is hyperactive in schizophrenia and mediates positive symptoms like delusions and hallucinations, 2) Mesocortical pathway, which is underactive in schizophrenia and mediates negative symptoms like loss of motivation and social withdrawal, 3) Nigrostriatal pathway, which controls motor function, and 4) Tuberoinfundibular pathway, which regulates prolactin secretion.

Why are D2 receptors clinically important in the treatment of psychotic disorders?

D2 receptors are important because they are the main targets of antipsychotic drugs. Blocking these receptors helps in reducing positive symptoms like delusions and hallucinations in psychotic disorders.

What is the difference between typical and atypical antipsychotics?

Typical antipsychotics (first generation) primarily block D2 receptors and are non-selective across dopamine pathways, while atypical antipsychotics (second generation) block both D2 receptors and serotonin receptors, with a lower risk of causing motor side effects and negative symptoms.

How do typical antipsychotics affect dopamine pathways, and what are the potential side effects?

Typical antipsychotics block D2 receptors across all dopamine pathways, which reduces positive symptoms but may worsen negative symptoms, cause extrapyramidal side effects like tremors and muscle rigidity, and increase prolactin levels, potentially causing sexual dysfunction and galactorrhea.

What is the difference between high-potency and low-potency typical antipsychotics?

High-potency typical antipsychotics bind more tightly to D2 receptors, providing stronger therapeutic effects at lower doses but causing more extrapyramidal side effects. Low-potency typical antipsychotics affect a wider range of receptors, leading to side effects like orthostatic hypotension, anticholinergic symptoms, and sedation.

Why do atypical antipsychotics tend to cause fewer motor side effects than typical antipsychotics?

Atypical antipsychotics tend to cause fewer motor side effects because they block D2 receptors only transiently and also block serotonin receptors, which helps to balance dopamine levels in brain areas that control movement.

What are some common side effects of atypical antipsychotics, and how do they vary between different drugs?

Common side effects of atypical antipsychotics include weight gain, hyperglycemia, sedation, and orthostatic hypotension. These vary based on the drug's receptor binding profile, such as strong serotonin 2C receptor affinity causing metabolic side effects (e.g., Clozapine and Olanzapine) and H1 receptor affinity causing sedation (e.g., Clozapine, Olanzapine, Quetiapine).

Why does Clozapine require periodic blood cell counts, and what is agranulocytosis?

Clozapine requires periodic blood cell counts because it can cause agranulocytosis, a serious condition where the bone marrow does not produce enough white blood cells, potentially leading to fatal infections.

Outlines

00:00

🧠 Overview of Antipsychotic Pharmacology

This paragraph introduces antipsychotics, a class of drugs used to treat psychotic disorders like schizophrenia, bipolar disorder, and severe depression. It explains the role of dopamine in the development of psychosis, focusing on the four major dopamine pathways: mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular. The paragraph also describes the types of dopamine receptors (D1-D5) and their relevance in psychotic disorders, particularly the importance of D2 receptors as the main targets of antipsychotic drugs. Finally, it provides an overview of the two types of antipsychotics: first-generation (typicals) and second-generation (atypicals).

05:03

💊 First-Generation vs. Second-Generation Antipsychotics

This paragraph details the differences between first-generation (typical) and second-generation (atypical) antipsychotics. First-generation antipsychotics primarily block D2 receptors in all dopamine pathways, which can reduce positive symptoms like hallucinations but also worsen negative symptoms and cause extrapyramidal side effects and prolactin-related issues. These drugs are further classified as high or low potency, with examples like Haloperidol (high potency) and Chlorpromazine (low potency). Second-generation antipsychotics block both D2 and serotonin 2A receptors, which helps reduce negative symptoms and minimize side effects such as extrapyramidal symptoms. Examples include Aripiprazole, Clozapine, and Risperidone. The paragraph also explains that atypical antipsychotics target additional receptors, leading to various side effects such as metabolic disturbances, sedation, and orthostatic hypotension, with specific examples like Clozapine's risk of agranulocytosis.

Keywords

💡Antipsychotics

Antipsychotics are a class of drugs used to treat psychotic disorders, such as schizophrenia, bipolar disorder, and severe depression. These drugs work by altering neurotransmitter functions in the brain, particularly dopamine, which plays a key role in the development of psychosis. In the video, antipsychotics are categorized into typical (first generation) and atypical (second generation) agents, each having distinct mechanisms and side effects.

💡Dopamine

Dopamine is a monoamine neurotransmitter that plays a key role in regulating mood, motivation, and motor functions. In the context of psychosis, the dopamine hypothesis suggests that an imbalance in dopamine pathways contributes to psychotic symptoms. The video explains how different dopamine pathways, such as the mesolimbic and mesocortical, are associated with different symptoms of schizophrenia and how antipsychotic drugs target dopamine receptors to alleviate symptoms.

💡Mesolimbic Pathway

The mesolimbic pathway is one of the four major dopamine pathways in the brain and is thought to be hyperactive in schizophrenia. This hyperactivity leads to positive symptoms of psychosis, such as hallucinations and delusions. In the video, this pathway is highlighted as a primary target of antipsychotics, as blocking dopamine receptors here can help reduce these positive symptoms.

💡Mesocortical Pathway

The mesocortical pathway is another dopamine pathway, which is underactive in schizophrenia, leading to negative symptoms such as lack of motivation and social withdrawal. Antipsychotics can sometimes worsen these symptoms by blocking dopamine receptors in this pathway, which complicates the treatment of schizophrenia, as described in the video.

💡Extrapyramidal Symptoms

Extrapyramidal symptoms (EPS) refer to drug-induced movement disorders, such as tremors, muscle rigidity, and difficulty with movement, often resembling Parkinson’s disease. These symptoms are linked to the blockade of dopamine receptors in the nigrostriatal pathway, as explained in the video. First-generation antipsychotics, especially high-potency agents, are more likely to cause these side effects.

💡Tuberoinfundibular Pathway

The tuberoinfundibular pathway is a dopamine pathway involved in the regulation of prolactin secretion, which affects sexual function and milk production. Antipsychotic drugs that block dopamine receptors in this pathway can lead to increased prolactin levels, causing side effects such as galactorrhea and gynecomastia. This pathway's role in side effects is discussed in relation to both typical and atypical antipsychotics in the video.

💡D2 Receptors

D2 receptors are a type of dopamine receptor that is the main target of antipsychotic drugs, particularly in the treatment of schizophrenia. The video emphasizes that typical antipsychotics primarily block D2 receptors across different dopamine pathways, which leads to both therapeutic effects and various side effects. Atypical antipsychotics also affect D2 receptors but in a more transient and selective manner, leading to fewer side effects.

💡Typical Antipsychotics

Typical antipsychotics, also known as first-generation antipsychotics, primarily block D2 receptors and are used to treat the positive symptoms of schizophrenia, such as delusions and hallucinations. However, they can cause significant side effects, including extrapyramidal symptoms and increased prolactin levels. The video contrasts these older agents with second-generation antipsychotics, explaining their stronger D2 receptor affinity.

💡Atypical Antipsychotics

Atypical antipsychotics, or second-generation antipsychotics, are a newer class of drugs that block both D2 dopamine receptors and serotonin receptors (specifically 5-HT2A). This dual action leads to fewer extrapyramidal side effects and helps improve negative symptoms of schizophrenia, as highlighted in the video. Examples include Clozapine and Risperidone, with additional receptor affinities leading to side effects like weight gain or sedation.

💡Extrapyramidal Disorders

Extrapyramidal disorders refer to a range of movement-related side effects caused by the blockade of dopamine receptors in the nigrostriatal pathway by antipsychotic drugs. The video discusses how these disorders, such as dystonia, tardive dyskinesia, and Parkinson’s-like symptoms, are more common with high-potency typical antipsychotics and less common with atypical antipsychotics, which have a lower affinity for D2 receptors.

Highlights

Antipsychotics are primarily used to treat psychotic disorders such as schizophrenia, bipolar disorder, and severe depression.

The dopamine hypothesis suggests that changes in dopamine function in the brain largely explain psychosis.

Dopamine affects the brain through four major pathways: mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular.

Hyperactivity in the mesolimbic pathway is associated with positive psychotic symptoms like delusions and hallucinations.

Underactivity in the mesocortical pathway is linked to negative symptoms such as loss of motivation and social withdrawal.

The nigrostriatal pathway controls motor function, and dopamine deficiency here can cause parkinsonian symptoms, while excess dopamine can cause tics.

In the tuberoinfundibular pathway, dopamine inhibits prolactin secretion, affecting milk production and sexual desire.

D2 receptors are the primary target of antipsychotic drugs, especially in the treatment of psychotic disorders.

First-generation antipsychotics, known as typicals, block D2 receptors but can worsen negative symptoms and cause motor dysfunction.

High-potency typical antipsychotics like Haloperidol produce stronger antipsychotic effects but also increase extrapyramidal side effects.

Low-potency antipsychotics like Chlorpromazine bind less tightly to D2 receptors and often affect other receptors, causing a range of side effects.

Second-generation antipsychotics, known as atypicals, block both D2 and serotonin receptors, reducing side effects and improving cognition.

Atypicals such as Aripiprazole and Clozapine occupy D2 receptors transiently, lowering the risk of motor-related side effects.

Clozapine, while effective, can cause agranulocytosis, a potentially fatal condition requiring regular blood monitoring.

Atypical antipsychotics can cause weight gain, metabolic disturbances, sedation, and orthostatic hypotension, depending on their receptor affinity.

Transcripts

in this lecture we are going to cover pharmacology of antipsychotics

so antipsychotics are a class of drugs used primarily to treat psychotic

disorders such as schizophrenia mania due to bipolar disorder and severe

depression now in order to gain better understanding of mechanism of action of

antipsychotic drugs first we need to discuss the role of dopamine in the

development of psychosis so the monoamine neurotransmitter dopamine

plays a key role in the so called 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

now dopamine has four major pathways by which it affects the brain

number one the mesolimbic pathway which is thought to be hyperactive in

schizophrenia and to mediate positive symptoms of psychosis such as delusions

and hallucinations number two mesocortical pathway which is

thought to be under active in schizophrenia and thus mediate negative

psychotic symptoms such as loss of motivation and social withdrawal

number three the nigrostriatal pathway which is part of the extrapyramidal nervous

system and controls motor function and movement deficiency of dopamine in this

pathway can lead to dystonia and parkinsonian symptoms while excess of

dopamine can lead to hyperkinetic movements such as tics and dyskinesias

the last major pathway number four is the tuberoinfundibular pathway

which controls prolactin secretion specifically dopamine in this pathway

inhibits prolactin release and as a reminder prolactin is a hormone that

enables milk production and is also involved in the control of sexual desire

and regulation of immune system now within those different pathways dopamine

interacts with specific receptors that mediate functional effects of dopamine

there are five primary types of dopamine receptors known as D1 D2 D3 D4 and D5

out of the five D1 and D2 receptors are found in the highest

density in nearly all of the pathways involved in psychotic disorders however

D2 receptors are the most clinically relevant because they are the

main targets of antipsychotic drugs now antipsychotics can be grouped into older

first generation agents known as typicals and the newer second-generation

agents known as atypicals the first generation typical antipsychotics all

share the same main therapeutic goal that is to block D2 receptors

furthermore typical antipsychotics are not selective for any of the four

dopamine pathways and thus will block D2 receptors in almost all areas of the

brain this has positive as well as negative consequences so blockade of

dopamine receptors in the mesolimbic pathway reduces positive symptoms such

as delusions and hallucinations which is beneficial

however blockade of dopamine receptors in the mesocortical pathway that is

already underactive in schizophrenia may cause worsening of negative symptoms

and thus lead to diminished energy lack of motivation restrictions

in emotional and verbal expressiveness and social disengagement furthermore

blockade of dopamine receptors in the nigrostriatal pathway may lead to

extrapyramidal disorders tardive dyskinesia and parkinson's-like symptoms

such as tremors muscle rigidity and difficulty in starting and stopping

movements lastly blockade of dopamine receptors in the tuberoinfundibular

pathway may cause increase in blood prolactin levels which then may lead to

galactorrhea gynecomastia and sexual dysfunction now based on their affinity

for D2 receptors typical antipsychotics are often subclassified as high potency

or low potency the examples of high potency antipsychotics are Haloperidol

Fluphenazine Prochlorperazine and Trifluoperazine the example of low

potency antipsychotic is Chlorpromazine so

generally speaking the high potency agents produce stronger antipsychotic

effect at relatively low doses however they also tend to cause more

extrapyramidal side effects and greater increase in prolactin levels on the

other hand the less selective low potency agents do not bind to D2

receptor as tightly as the high potency agents and generally affect a range of

other receptors including alpha-adrenergic cholinergic and histamine

receptors this can result in a variety of side effects for example blockade of

alpha-adrenergic receptors can lead to orthostatic hypotension blockade of

muscarinic receptors can lead to anticholinergic symptoms such as dry

mouth blurred vision difficulty urinating and constipation and blockade

of H1-histamine receptors can lead to sedation and some weight gain now let's

move on to the second generation atypical antipsychotics in contrast to

typical antipsychotics that 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 that need it furthermore

atypicals occupy D2 receptors transiently and dissociate quickly

allowing for relatively normal dopamine neurotransmission this modest D2

receptor blockade in combination with serotonin receptor blockade is thought

to significantly lower the incidence of extrapyramidal side effects as well as

decrease negative symptoms and improve cognition compared to typical agents the

examples of atypical antipsychotics are Aripiprazole Clozapine Lurasidone

Olanzapine Quetiapine Risperidone and Ziprasidone

now in addition to dopamine and serotonin 2A receptor blockade atypical

antipsychotics also bind to many other targets including other subtypes of

serotonin receptors as well as histamine alpha-adrenergic and muscarinic receptors as a

result the side-effects of second-generation agents can vary

depending on the drug's receptor binding profile so for example atypical

antipsychotics that have strong affinity for serotonin receptors subtype 2C

such as Clozapine and Olanzapine may cause metabolic side effects including

weight gain hyperglycemia and dyslipidemia agents that have strong

affinity for H1 receptors such as Clozapine Olanzapine and Quetiapine

may cause sedation and may also contribute to weight gain agents that

have significant affinity for alpha-1-adrenergic receptors such as Clozapine

and Risperidone may cause orthostatic hypotension in addition to that out of

all second-generation agents Risperidone seems to have the strongest affinity for

D2 receptors and because of that it has the highest potential to induce

extrapyramidal side effects and hyperprolactinemia lastly Clozapine is

the only antipsychotic that can cause serious condition called agranulocytosis

that occurs when the bone marrow does not produce enough white blood

cells called granulocytes because this condition can be fatal periodic blood

cell counts must be performed to ensure patient safety and with that I wanted to

thank you for watching I hope you enjoyed this video and as always stay

tuned for more