AntiPsychotic Drugs: Basics

Question 1

What is Psychosis?

Answer 1

Sustained mental state of impaired contact with reality

Question 2

What is schizophrenia?

Answer 2

Chronic psychotic disorder characterized by disturbed behavior, thinking, emotions and perceptions

Question 3

What are the negative, positive and cognitive symptoms associated with schizophrenia?

Answer 3

Positive: seems to reflect an excess of normal functions: hallucinations and delusions, disorganized speech, and abnormal motor behavior
Negative: Reflect diminution or loss of normal functions: blunted affect, poverty of speech, diminished motivation and social withdrawal
Cognitive: include deficits in working memory and cognitive control of behavior

Question 4

What is the effect of dopamine on the negative and positive symptoms of schizophrenia?

Answer 4

Drugs that increase dopaminergic activity increase or produce positive psychotic symptoms (amphetamines or cocaine)
Drugs that decrease dopaminergic activity decrease or stop positive symptoms

Question 5

There are 4 well defined dopamine pathways in the brain. The first is the mesolimbic pathway. What are some features of this pathway?

Answer 5

1. Projects from the midbrain to the limbic system
2. This pathways is thought to have an important role in emotional behaviors
3. Hyperactivity of this pathway is believed to account for positive psychotic symptoms
4. Blockade of postsynaptic D2 receptors in this pathway is believed to mediate the antipsychotic efficacy of antipsychotic drugs and their ability to diminish positive symptoms.

Question 6

The second pathway is the mesocortical pathway. What are features of this pathway?

Answer 6

1. Projects from the midbrain to the prefrontal cortex
2. Negative and Cognitive Symptoms may be due to reduced activity of this pathway
3. Blockade of D2 receptors in the mesocortical pathway may cause or worsen negative and cognitive symptoms. It may cause emotional blunting and cognitive problems.

Question 7

The third pathway is the nigrostriatal pathway. What are features of this pathway?

Answer 7

1. Projects from the substantia nigra to the basal ganglia
2. It controls motor movements
3. When dopamine receptors are blocked in postsynaptic projections of this system disorders of movement can appear
4. This pathway is part of the extrapyramidal nervous system. Therefore motor adverse effects associated with blockade of D2 receptors in this system are called extrapyramidal reactions (EPRs)–Acute dystonia, akathisia, and parkinsonian like syndrome.

Question 8

The fourth pathway is the tuberoinfundibular pathway. What are features of this pathway?

Answer 8

1. Projects from the hypothalamus to the anterior pituitary
2. Dopamine released from these neurons physiologically inhibits prolactin secretion
3. Blockage of D2 receptors in this pathway leads to an increase in prolactin levels, which may cause galactorrhea.

Question 9

Now moving on to the drugs. There are classical and atypical antipsychotics. What are the classical antipsychotics?

Answer 9

Chlorpromazine (low potency drug)
Thioridazine (low potency drug)
--less likely to produce extrapyramidal reactions and more likely to produce sedation and postural hypotension
Fluphenazine (high potency) 
Haloperidol (high potency)
--produce extrapyramidal reactions

Question 10

The atypical antipsychotics are currently the most widely used type of antipsychotic drugs. What are these drugs?

Answer 10

Clozapine
Risperidone
Olanzapine
Quetiapine
Aripiprazole

Question 11

What is the MOA for the classical antipsychotic drugs?

Answer 11

Block dopamine receptors in the brain and in the periphery.
–D1 like dopamine receptors: D1 and D5: activate adenylyl cyclase
–D2 like dopamine receptors: D2, D3, D4: inhibit adenylyl cyclase
The efficacy of the traditional neuroleptic drugs correlates closely with their ability to block D2 receptors in the mesolimbic pathway.

Question 12

Now for the atypical antipsychotic drugs. Give some examples of the drugs and their affinity for the various receptors

Answer 12

Clozapine (protype atypical): has high affinity for D1, D4, 5HT2, muscarinic and alpha adrenergic receptors but it also has a D2 blocker
Risperidone: blocks 5HT2 to a greater extent than it does D2

Question 13

What are the common properties of atypical antipsychotics?

Answer 13

1. Exhibit dual antagonism at 5-HT2A and D2 receptors. They are referred to as serotonin-dopamine antagonists (SDA)
2. Appear to exert part of their action by blocking 5HT receptors
3. Much less likely to cause extrapyramidal reactions than classical agents
4. Less likely to cause tardive dyskinesia
5. Less likely to cause increases in prolactin
6. More effective at treating negative symptoms
7. Effective in treatment of refractory populations.

Question 14

What are some properties of Clozapine?

Answer 14

1. Atypical Prototype

2. Least likely to induce EPR (also quetiapine has low EPR side effects)

Question 15

What are properties of Aripiprazole?

Answer 15

Partial agonist at D2 and 5HT1A receptors and an antagonist at 5HT2A receptors
–activity due to its metabolite dehydroaripiprazole

Question 16

What are properties of Risperidone?

Answer 16

Much more potent antidopaminergic and much less potent antimuscarinic activity than clozapine
–can cause extrapyramidal reactions (rare at therapeutic dosese) and hyperprolactinemia

Question 17

The actions of antipsychotics reflect the blockade of dopamine and/or serotonin receptors. But many block muscarinic, alpha 1 adrenergic receptors, and H1 receptors, producing side effects. However what are the actions of these antipsychotics given what they block?

Answer 17

1. Reduce hallucinations an agitation by blocking dopamine receptors in mesolimbic system
2. Calming effect and reduce spontaneous physical movement
3. Dont depress intellectual function, and motor incoordination is minimal
4. Onset is within the first 24h of treatment and the magnitude of this action grows with time.

Question 18

What are the antiemetic effects of the antipsychotic drugs?

Answer 18

With the exception of Aripiprazole (atypical) and Thioridazine (classical)
–blockade of D2 receptors of the chemoreceptor trigger zone of the medulla

Question 19

Most antipsychotic drugs are almost completely metabolized, mainly by CYP2D6, CYP1A2 and CYP3A4. What does this mean?

Answer 19

At typical clinical doses, antipsychotics do not usually interfere with the metabolism of other drugs

Question 20

Explain the uses for Fluphenazine Decanoate (classical), Haloperidol Decanoate (Classical), and Risperidone Microspheres (atypical).

Answer 20

Slow release (up to 2 to 4 weeks)

• -administered IM
• -used to treat outpatients and individuals who are non compliant with oral meds
• -risk of EPR is lower

Question 21

Now lets go through the adverse effects of the antipsychotic drugs. First are the neurological effects. Extrapyramidal reactions are a side effect, explain why.

Answer 21

Inhibitory effects of dopaminergic neurons are normally balanced by the excitatory actions of cholinergic neurons. Blocking dopamine receptors alters this balance, causing a relative excess of cholinergic influence and resulting in extrapyramidal motor effects.

Question 22

Extrapyramidal reactions are associated with high D2 potency. So what drugs are more and less associated with extrapyramidal reactions then?

Answer 22

Haloperidol and Fluphenazine: have a high affinity for D2 receptors in the basal ganglia (so more extrapyramidal reactions). Low anticholinergic activity
Chlorpromazine and Thioridazine: have a lower affinity for D2 receptors (so less extrapyramidal reactions). Strong anticholinergic activity

Question 23

Atypical antipsychotic drugs have a lower or higher potential for extrapyramidal symptoms? and what are these symptoms?

Answer 23

Atypical Antipsychotic drugs have a low potential
Extrapyramidal reactions include: typical Parkinson’s syndrome, acute dystonic reactions, akathisia, and tardive dyskinesia.

Question 24

What can parkinsonism be treated with?

Answer 24

Antimuscarinic
–benztropine or trihexyphenidyl with diphenhydramine or with amantadine
Never give LEVODOPA to these patients

Question 25

What is acute dystonia and akathisia treated with?

Answer 25

Acute Dystonia (sustained involuntary muscle contractions): benztropine, trihexyphenidyl or diphenhydramine 
Akathisia (Restlessness) : reduction of dosage or a change of the antipsychotic drugs. Clonazepam or Propranolol

Question 26

Late occurring syndrome of choreoathetoid movements is the most important adverse effect of antipsychotic drugs. Patients display involuntary movements including lateral jaw movements. Potentially irreversible disorder. What is it due to?

Answer 26

Long term Dopamine receptor blockage causing dopamine receptors to up regulate

Question 27

When tardive dyskinesia is diagnosed what is the first step?

Answer 27

Discontinue the antipsychotic drug or reduce the dose

–clozapine has been recommended as treatment for patients with tardive dyskinesia who require antipsychotics

Question 28

As a review which drugs have no or very little EPR risk and which drugs have the most?

Answer 28

Atypical
–clozapine and Quetiapine: very little to no
Classical:
–Fluphenazine and Haloperidol: high potency

Question 29

Another rare but potentially fatal reaction to antipsychotic drugs is Neuroleptic malignant syndrome. What is it characterized by?

Answer 29

Severe rigidity, tremor, hyperthermia, altered mental status, autonomic instability, elevated WBC, elevated CK, and nephrotoxicity
–results from excessively rapid blockade of postsynaptic dopamine receptors
Tx: discontinue the neuroleptic and supportive therapy
Dantrolene or Bromocriptine can be helpful

Question 30

Finally sedation and seizures are side effects of antipsychotic drugs, which drugs specifically?

Answer 30

Sedation: low potency antipsychotics and atypical agents due to blockade of H1 receptors
Seizures: chlorpromazine and clozapine