Antipsychotics

Question 1

Antipsychotics

Answer 1

Primarily used in treatment of schizophrenia but used for any disorder involving psychotic symptoms

• major tranquilizer is the original name (barbs and benzos minor tranquilizers) - antipsychotic effects were discovered when major tranquilizers were used to quiet institutionalized mental pts
• called neuroleptics- based on tendency to produce neurological side effects

Question 2

Schizophrenia positive symptoms

Answer 2

hallucinations (auditory), delusions (inappropriate beliefs), disorganized

Question 3

Schizophrenia negative symptoms

Answer 3

flat or inappropriate effect, social isolation or withdrawal, alogia (poverty of speech), avolition, anhedonia, cognitive deficits

Question 4

Pathogenesis of schizophrenia

Answer 4

• neurodevelopmental
• 50% heritability
• likely involves aberrant dopaminergic, glutamatergic, and/or serotonergic activity

Question 5

Dopamine neurochemical hypothesis

Answer 5

• positive symptoms arise from hyperactivity of CNS dopamine systems- mesolimbic and mesocortical (from ventral tegmental area to cortical and limbic areas)
• thought to be because L-DOPA can cause psychosis (too much dopamine), amphetamine (releases and blocks reuptake of dopamine) can cause psychosis and makes schizophrenics worse

Question 6

Serotonin hypothesis

Answer 6

5-HT2a and 5-HT2c receptors mediate hallucinogenic effects

Question 7

Glutamate

Answer 7

-phencyclidine and ketamine produce effects that resemble aspects of schizophrenia and exacerbate symptoms in schizophrenics

Question 8

Mechanism of action of antipsychotics

Answer 8

true mechanism is unknown

• all are D2 dopamine receptor antagonists
• serotonin receptors and/or novel D2 like receptors (D3 or D4) may be involved
• also interact with other receptors (a1. Ach, histamine, etc) which contributes to side effects and varies with each drug- dirty drugs

Question 9

Pharmacological effects of antipsychotics

Answer 9

initial- sedation, decreased agitation

In schizophrenics- positive symptoms improve over weeks to months of treatment (problem with dopamine hypothesis because of compensatory changes leading to upregulation of dopamine receptors lead to antipsychotic effects)

Negative symptoms- improved by newer drugs, but older typical drugs have little effect

In normal persons- dysphoria, disinterest, blunted affect

Antiemetic- blockage of dopamine receptors in CTZ, not useful for motion sickness

Question 10

Early side effects

Answer 10

Neurological- extrapyramidal effects (EPS)- can cause dystonia (1-5 days), akathisia (5-60 days),

parkinsonian symptoms (tremor, rigidity, bradykinesia; 5-30 days) due to blockage of striatal dopamine receptors –can be treated with anticholinergics

Question 11

More side effects

Answer 11

increased prolactin release due to blockade of D2 receptors- amenorrhea, gynecomastia, galactorrhea (dopamine inhibits prolactin release)

Weight gain, metabolic syndrome, diabetes

anti-histaminergic effects- sedation
orthostatic hypotension and sexual dysfunction- alpha adrenergic

anticholinergic effects (dry mouth)

CV alterations- prolonged QT

Blurred vision, retinitis pigmentosa (thioridazine)

neuroleptic malignant syndrome- treated with dantrolene- malignant hyperthermia due to impaired muscle activity and sweating

decreased seizure threshold

poikilothermy- can lead to hypothermia

Question 12

long term side effects

Answer 12

tardive dyskinesia- abnormal movements and facial disfigurement, frequently irreversible
-may be due to long term dopaminergic receptor blockade

perioral tremor (rabbit syndrome)

blood dyscrasias- agranulocytosis can occur with clozapine and some phenothiazines

Question 13

What drug causes agranulocytosis

Answer 13

clozapine

Question 14

pharmacokinetics

Answer 14

IM, IV, PO

Highly lipophilic so can get into brain

Question 15

Drug interactions

Answer 15

potentiate CNS depressants- barbiturates

• block dopamine agonists
• modify cv drugs
• inc risk of seizures with other drugs

Question 16

Typical antipsychotics

Answer 16

• Effective against positive, but not negative symptoms
• Produce EPS and tardive dyskinesia
• all are D2 antagonists and are antagonists at variety of other receptors- confers unique SE

Question 17

Phenothiazines

Answer 17

typical antipsychotics
Chlorpromazine- first antpsychotic
Fluphenazine
Thioridazine

Question 18

Haloperidol

Answer 18

typical antipsychotic

most widely prescribed antipsychotics
relatively more selective for dopamine receptors- highest incidence of EPS

also used for tourettes, huntingtons

Question 19

Thiothixene

Answer 19

Other structure of typical antipsychotic

Question 20

Atypical antipsychotic

Answer 20

• No EPS or tardive dyskinesia, antagonist at 5HT2 receptors
• Clozapine- 5HT2>D2
• activity at lots of receptors
• some effect on negative symptoms as well as positive symptoms

agranulocytosis in abt 3% of pts

approved ONLY for treatment resistant pts who must receive regular blood tests

Question 21

Newer antipsychotic

Answer 21

• trying to achieve atypical profile
• significant 5-HT2 antagonist activity
• generally improved side effects because of fewer extraneous receptor interactions

Question 22

Resperidone

Answer 22

• newer antipsychotic
• 5HT2=D2
• EPS at higher doses, does not effect negative symptoms

Question 23

Lurasidone

Answer 23

5HT2, D2, 5HT7
-newer antipsychotic
less incidence of EPS

also used for depression in bipolar disorder

Question 24

Olanzepine

Answer 24

newer 
even less EPS 
5HT2> D2
high incidence of weight gain and metabolic syndrome
may improve negative symptoms

Question 25

Quetiapine

Answer 25

newer antipsychotic 5Ht2=D2 high incidence of weight gain and metabolic syndrome may improve negative symptoms

Question 26

Ziprasidone

Answer 26

newer antipsychotic D2, 5-HT2A, 5-HT1d antagonist 5-HT1a agonist

Question 27

Aripiprazole

Answer 27

D2, 5HT1a partial agonist 5-HT2A antagonist partial agonism at D2 receptors may allow for sufficient stimulation to prevent EPS while preventing over stimulation used for refractory depression

Question 28

Other uses of antipsychotics

Answer 28

management of agitation and psychotic symptoms in acute mania and bipolar disorder, delirium, depentia, alcoholic hallucinosis (during heavy drinking, not withdrawal because of inc risk of seizures) -maintenance of bipolar disorder dopamine agonist induced psychotic symtpoms- parkinson's tourettes, huntingtons, refractory depression, depression in bipolar disease