Pharmacology of Anitpsychotics

Question 1

Define Psychosis

Answer 1

the inability to distinguish between the internal experience (mind) and the external experience of the environment (reality)

Question 2

What are the signs/symptoms of psychosis?

Answer 2

delusions and hallucinations, but may also include disorganized speech, disorganized behavior, or gross distortions of reality

Question 3

What are the diagnosis requirements for schizophrenia?

Answer 3

1. two or more of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms
2. social and/or occupational dysfunction
3. continuous signs of disturbances persist at LEAST 6 MONTHS
4. rule out drugs or medical conditions as cause

Question 4

What are positive symptoms of schizophrenia?

Answer 4

-hallucinations: sensory perceptions unconnected to external stimuli (typically auditory)
-delusions: fixed false belief that is not shared by others in culture
-disorganized thoughts and speech: rambling, mutism, etc.
-abnormal motor behavior: strange posture or catatonic

Question 5

What drugs may induce similar psychotic symptoms to schizophrenia?

Answer 5

-cocaine, amphetamine (dopamine agonist, NE agonist)
-hallucinogenic drugs (serotonin agonist)
-anticholinergic drugs (Ach antagonism)
-dissociative anesthetic (glutamate N-methyl-D-aspartate antagonism)

Question 6

Describe the Glutamate hypothesis in Schizophrenia

Answer 6

antagonists of the NMDA glutamate receptor, such as PCP and ketamine, produce behavioral changes in humans (psychosis, hallucinations, etc) resulting in hypofunction of NMDA receptors are hypothesized to be involved in schizophrenia

Question 7

What are the 2 classes of DA receptors?

Answer 7

-D1 (and D5) are Galpha(s) receptors that increase cAMP and are located post synaptically
-D2 (and D3 and D4) are Galpha(i) receptors that decrease cAMP and are located both pre- and post synaptically

Question 8

What neurotransmitters are implicated in Psychosis/Schizophrenia?

Answer 8

dopamine, serotonin, glutamate

Question 9

What drugs are first generation antipsychotics?

Answer 9

chloropromazine and haloperidol

Question 10

What first generation antipsychotic is considered low potency?

Answer 10

chlorpromazine

Question 11

What first generation antipsychotic is considered high potency?

Answer 11

haloperidol

Question 12

What are the side effects of low potency first generation antipsychotics?

Answer 12

low incidence of neurological side effects (ACh block, D2 block, and serotonin (5HT) block), but high incidence of autonomic side effects (sedation, alpha1 block)

Question 13

What are the side effects of high potency first generation antipsychotics?

Answer 13

fewer autonomic side effects (alpha1 block) but higher frequency of neurological and endocrinological side effects (D2 block, serotonin (5HT) block)

Question 14

How do antipsychotics treat positive symptoms of schizophrenia?

Answer 14

overactive mesolimbic dopamine neurotransmission induces positive symptoms so antagonism of D2 dopamine receptors normalize dopamine neurotransmission to treat positive symptoms

Question 15

How do antipsychotics induce Parkinsonism (extrapyramidal symptoms)?

Answer 15

dopamine receptors in the nigrostriatal system are also blocked and blockade of D2 receptors in the striatum causes imbalance of dopamine and produces parkinsonian-like effects

Question 16

What can occur with prolonged treatment of D2 blockers?

Answer 16

supersensitivity (upregulation) of D2 receptors which causes striatal GABAergic efferent becomes very reduced and produces tardive dyskinesia (abnormal movement- typically in the face)

Question 17

What are the pros of using Clozapine to treat schizophrenia?

Answer 17

first atypical antipsychotic
-higher blocking potency at 5HT receptor
-no D2 receptor supersensitivity, less extrapyramidal symptoms (EPS)
-better use against negative symptoms and for treatment-resistance schizophrenia

Question 18

What are the risks associated with Clozapine?

Answer 18

agranulocytosis, diabetes

Question 19

Why is Clozapine less likely to induce extrapyramidal symptoms (EPS)?

Answer 19

1. less affinity for blocking D2 receptors and somewhat selective blocking D2 in mesolimbic pathway
2. higher blocking potency at 5-HT2 (serotonin) than D2 and serotonin acts as a modulator to regulate DA release. By blocking 5HT2a receptors -> DA release is increased in the nigrostriatal pathway = reduce EPS

Question 20

What drugs are known as atypical antipsychotics?

Answer 20

-clozapine (first one, but typically reserved to last line treatment)
-risperidone
-olanzepine
-quetiapine
-ziprasidone

Question 21

What antipsychotics act as D2 receptor partial agonists?

Answer 21

-aripiprazole
-brexipiprazole
-cariprazine

Question 22

What is the advantage of partial agonist activity at D2 receptors for antipsychotic activity?

Answer 22

decrease dopamine activity in accumbens (where it is too high) and increased dopamine in the frontal cortex (where it is too low)

Question 23

Describe Acute Dystonia:

Answer 23

-spasm of muscles of the tongue, face, neck, and back
-typically occurs 1-5 days after beginning antipsychotics (usually young, antipsychotic naive pts)
-occurs due to acute DA antagonism

Question 24

Describe Akathisia:

Answer 24

-motor restlessness (not anxiety or agitation)
-occurs 5-60 days after beginning therapy

Question 25

Describe Parkinsonism (extrapyramidal symptoms (EPS)):

Answer 25

-bradykinesia, rigidity, tremor, mask face, shuffling gait
-occurs 5-30 days after beginning treatment (elderly are the most at risk)
-occurs due to DA antagonism

Question 26

Describe Neuroleptic Malignant Syndrome (NMS):

Answer 26

-characterized by catatonia, stupor, fever, unstable blood pressure, myoglobinemia
-can occur within weeks of beginning treatment and is persistent after stopping antipsychotics
-CAN BE FATAL! (high mortality)- stop drug immediately
-bromocriptine or dantrolene can help

Question 27

Describe Tardive Dyskinesia:

Answer 27

-oral-facial dyskinesias
-occurs after months or years of treatment (20% of pt experience this)
-occurs due to dopamine receptor supersensitivity= striatal GABAergic efferent becomes reduced

Question 28

What can be used to treat tardive dyskinesia?

Answer 28

VMAT2 inhibitors (valbenazine and deutetrabenazine)

Question 29

What autonomic side effects may occur from antipsychotics?

Answer 29

-orthostatic hypotension (alpha1 blockade) which can be associated with reflex tachycardia (dangerous in the elderly)
-altered sexual function
-anticholinergic effects (dry mouth, blurred vision, constipation and urinary retention)