A.27. 1st generation ("typical") antipsychotic agents

Question 1

definition of psychosis

Answer 1

collection of psychological symptoms resulting in a loss of contact with reality

Question 2

positive symptoms for psychosis

Answer 2

thought disorders
delusions 
hallucinations 
paranoia/ catatonia 
disorganized speech

Question 3

negative symptoms for psychosis

Answer 3

amotivation
social withdrawal
poverty of speech (alogia)
anhedonia (inability to feel pleasure)

Question 4

types of psychosis

Answer 4

1. schizophrenia
2. affective psychoses
3. other: schizoaffective, drug-induced, psychosis from organic reasons (dementia, parkinson)

Question 5

what are the hypothesizes of psychosis?

Answer 5

1. dopamine
2. serotonin
3. dysregulation

Question 6

what does the serotonin hypothesis say?

Answer 6

cause of the disease is excessive serotonergic stimulation in the cerebral cortex

Question 7

what does the dysregulation hypothesis say?

Answer 7

psychosis is a multifactorial condition, affected by multiple pathways and neurotransmitter interactions (GABA, glutamate, 5-HT, dopamine)

Question 8

what does the dopamine hypothesis say?

Answer 8

changes in dopamine function that cause psychosis:
mesocortical pathways (↓ activity --> negative symptoms)
mesolimbic pathways ( ↑ activity --> positive symptoms) 
nigrostriatal pathway ( extrapyramidal motor function)
tuberoinfundibular pathways (control of prolactin release)
chemoreceptor trigger zone (emesis)

Question 9

when does psychosis start?

Answer 9

mostly in young adults ~20

Question 10

what are the clinical uses of antipsychotic agents? name 3

Answer 10

1. treatment of schizophrenia and other psychotic disorders–> symptomatic, allow them to be in society
2. initial treatment of bipolar disorders (atypical)–> usually in combination with lithium
3. management of toxic (acute) psychosis due to overdose by CNS stimulants
4. Tourette’s syndrome
5. Huntingtons disease
6. Alzheimer and Parkinson (atypical)
7. antiemetic activity

Question 11

do typical agents have an effect on negative symptoms?

Answer 11

no

Question 12

disorders are characterized as psychotic or on the schizophrenia spectrum when..

Answer 12

either positive and negative symptoms appear

Question 13

pharmacokinetic properties of typical antipsychotic agents (1st generation)

Answer 13

good oral bioavailability
parenteral preparations for both rapid initiation of therapy and depot formulations
long T1/2–> once-daily dosing
hepatic P450 metabolism
↑ lipid solubility –> penetrates the CNS

Question 14

what are the groups of typical antipsychotic agents (1st gen’)?

Answer 14

1. phenothiazines- oldest
2. butyrophenones
3. thioxanthene

Question 15

list the phenothiazines

Answer 15

chlorpromazine
thioridazine
fluphenazine

Question 16

list the butyrophenones

Answer 16

haloperiodol

droperiodol

Question 17

what is flupentixol?

Answer 17

it’s a thioxanthene

Question 18

give the typical agents with low potency D₂ blockage?

Answer 18

chlorpromazine

thioridazine

Question 19

give the typical agents with high potency D₂ blockage?

Answer 19

haloperidol
droperidol
flupentixol

Question 20

give the typical agents with no 5-HT blocking?

Answer 20

haloperidol

Question 21

give the typical agents with 5-HT and no muscarinic blocking?

Answer 21

droperiodol

flupentixol

Question 22

give the typical agents with muscarinic blocking?

Answer 22

chlorpromazine

thioridazine

Question 23

give the typical agents with 𝝰₁ blocking?

Answer 23

chlorpromazine
thioridazine
haloperidol

Question 24

give the typical agents with no 𝝰₁ blocking?

Answer 24

droperidol

Question 25

give the typical agents with histamine blocking and high sedation effect?

Answer 25

chlorpromazine
thioridazine
droperidol

Question 26

give the typical agents without histamine blocking?

Answer 26

haloperidol

Flupentixol

Question 27

give the typical agents with low sedation effect?

Answer 27

haloperidol

flupentixol

Question 28

SE of chlorpromazine?

Answer 28

corneal depositions (high dose)

Question 29

SE of thioridazine?

Answer 29

cardiotoxicity (prolonged QT, torsade)

retinal depositions

Question 30

is Fluphenazine available as depot injection?

Answer 30

yes

Question 31

for what is haloperidol used and what is the dose?

Answer 31

acute psychotic disorders (delirium), 5mg IM

Question 32

what are the SE of haloperidol?

Answer 32

neuroleptic malignant syndrome (NMS) and TD

strong EPS

Question 33

what is the use of droperidol?

Answer 33

1. anti-emetic use
2. used in neuroleptanalgesia (in combination with fentanyl)
3. sedative effect- used in general anesthesia

Question 34

adverse effects and toxicity of typical agents

Answer 34

extrapyramidal symptoms (EPS)
akathisia 
tardive dyskinesia (TD)
acute dyskinesia 
dysphoria 
hyperprolactinemia 
weight gain
neuroleptic malignant syndrome (NMS)
autonomic abnormalities

Question 35

what is dysphoria and what is the mechanism?

Answer 35

worsens negative symp of schizophrenia

dopamine receptor blockade

Question 36

what is the management of dysphoria?

Answer 36

dose reduction

Question 37

what are extrapyramidal symptoms? EPS

Answer 37

Drug-induced parkinsonism
(weeks after the initiation of treatment ):
bradycardia
tremor (perioral–> ‘rabbit’s mouth)
rigidity (‘cogwheel rigidity’)
dystonia - involuntary, abnormal muscle spasm and posture

Question 38

what is the mechanism of EPS?

Answer 38

dopamine receptor blockade

Question 39

management of EPS

Answer 39

dose reduction 
antimuscarinic agents (biperiden)

Question 40

what is akathisia?

Answer 40

can’t sit, state of agitation and restlessness

Question 41

what is tardive dyskinesia (TD)

Answer 41

involuntary, repetitive movements

develops after months- years of antipsychotic therapy, usually irreversible

Question 42

what is acute dyskinesia?

Answer 42

immediate-torticollis (neck muscles stuck down), oculogyric (eye is stuck up), tongue automatisms (repetitive movements)

Question 43

mechanism of akathisia

tardive and acute dyskinesia

Answer 43

dopamine receptor hypersensitivity

Question 44

treatment of akathisia

tardive and acute dyskinesia

Answer 44

antihistamines (diphenhydramine)
atypical antipsychotics (tiapride)

Question 45

mechanism of hyperprolactinemia?

Answer 45

dopamine receptor blockade

Question 46

presentation of hyperprolactinemia

Answer 46

gynecomastia
amenorrhea- galactorrhea syndrome
impotence
infertility

Question 47

reason of weight gain

Answer 47

H₁ and 5-HT blockade

Question 48

presentation of thermo-regulation abnormalities (neuroleptic malignant syndrome–> NMS)

Answer 48

muscle rigidity, rhabdomyolysis 
extreme catatonia 
impairment of sweat
malignant hyperthermia 
fever
altered mental status 
autonomic instability

Question 49

management of neuroleptic malignant syndrome–> NMS

Answer 49

Diazepam 
dantrolene (RYR inhibitor)
bromocriptine (D₂ agonist)
discontinue causative agent
stabilize BP, cool the patient

Question 50

what is the presentation of autonomic abnormalities?

Answer 50

loss of accommodation (blurred vision)
dry mouth
urinary retention, constipation
orthostatic hypotension

Question 51

what is the mechanism of autonomic abnormalities?

Answer 51

muscarinic and 𝝰- adrenergic blockade