lecture 53

Question 1

what are the implications that arise from the fact that multiple receptors can be targeted for beneficial antipsychotic activity?

Answer 1

unable to predict effectiveness of each therapy for individual pt
need to individualize therapy based on pt response
multiple receptors –> many SE –> poor adherence

Question 2

what are the critical NT targets of haloperidol?

Answer 2

D2 > D4 > 5HT2a

Question 3

what are the critical NT targets of aripiprazole?

Answer 3

D2 = 5HT2a > D4

Question 4

what are the critical NT targets of clozapine?

Answer 4

D4 > 5HT2a > D2

Question 5

what are the critical NT targets of quetiapine?

Answer 5

D2 > 5HT2a

Question 6

what are the critical NT targets of olanzapine?

Answer 6

5HT2a > D4 > D2

Question 7

what are the critical NT targets of chlorpromazine?

Answer 7

5HT2a > or = D2

Question 8

what are the autonomic manifestations and corresponding mechanism of antipsychotics?

Answer 8

muscarinic cholinoreceptor blockade – dry mouth, constipation, difficulty urinating
alpha adrenoreceptor blockade – orthostatic hypotension

Question 9

what are CNS manifestations and corresponding mechanism of antipsychotics?

Answer 9

DA receptor blockade – parkinsonian’s syndroma, akathasia, dystonias
supersensitivity of DA receptors – tardive dyskinesia
muscarinic blockade – toxic confusional state
histamine receptor blockade – sedation

Question 10

what do typical (first-generation) antipsychotics target?

Answer 10

D2 antagonist –> effect mesolimbic system

Question 11

what drugs are typical antipsychotics?

Answer 11

drugs that have a chemical structure with a phenothiazine nucleus (like chlorpromazine) or chemical structure with a butyrophenone (like haloperidol)

Question 12

why are typical antipsychotics no longer a first line drug?

Answer 12

chlorpromazine has multiple undesired targets (such as being an antihistaine)
haloperidol also has unfavorable SE (EPS)

Question 13

how does butyrophenone antipsychotics differ from phenothiazine antipsychotics?

Answer 13

butyrophenone (haloperidol) is more selective D2 antagonist

Question 14

what is the delay phase?

Answer 14

blockade at postsynaptic D2 receptors, initially offset by antagonist to D2 autoreceptors
similar to bell curve

Question 15

what is the antagonism phase?

Answer 15

D2 receptors are internalized (desensitization) and D2 autoreceptors response better to DA inhibitory effect (sensitization)
similar to linear

Question 16

how does D2 antagonist affect the mesolimbic?

Answer 16

primary therapeutic effect for antipsychotics

Question 17

for typical antipsychotics, what % of receptor occupancy has what effect?

Answer 17

70-80% – therapeutic efficacy
over 80% – extrapyramidal symptoms (EPS)

Question 18

what is action of D2 antagonist in the basal ganglia?

Answer 18

motor effects
EPS

Question 19

what is the action of D2 receptor antagonist in the mesocortical?

Answer 19

hypofunction in schizophrenia
antagonist may exacerbate cognitive deficits

Question 20

what is the action of D2 antagonist in the hypothalamus and endocrine systems?

Answer 20

hyperprolactinemia

Question 21

what is the action of D2 antagonist in the medulla?

Answer 21

chemoreceptor trigger zone
anti-emetic effect

Question 22

when does EPS appear?

Answer 22

early so in the days/weeks after start of treatment
reversible

Question 23

what are the symptoms of EPS?

Answer 23

dystonia (increased muscle tone)
pseudoparkinsonism (muscle rigidity)
tremor
akathisia (restlessness)

Question 24

what drugs are used to treat EPS?

Answer 24

anticholinergic agents (benztropine, trihexyphenidyl, akineton)
antihistamines (benadryl)
amantadine
beta-blockers (propranolol, specifically for akathisia)

Question 25

when does tardive dyskinesia appear?

Answer 25

late (months to years) IRREVERSIBLE

Question 26

what are the symptoms of tardive dyskinesia?

Answer 26

rhythmic involuntary movements of the mouth choreiform movements (irregular purposelessness) athetoid (worm-like) movements axial hyperkinesia

Question 27

what is the MOA of tardive dyskinesia?

Answer 27

not well understood possible neuroadaptive response so antagonist induced supersensitivity of receptors to dopamine?

Question 28

how should pts be monitored for tardive dyskinesia?

Answer 28

AIMS (abnormal involuntary movement scale) checked every 6 months

Question 29

what are the treatments of tardive dyskinesia?

Answer 29

prevention (least risky agent at lowest dose possible and monitor) reduce dose of current agent change to different drug eliminate anticholinergic drugs VMAT2 inhibitors

Question 30

what drugs are VMAT2 inhibitors?

Answer 30

tetrabenazine valbenazine deutrabenazine

Question 31

when does neuroleptic malignant syndrome (NMS) appear?

Answer 31

few days to 2 weeks after start

Question 32

how does NMS present?

Answer 32

EPS symptoms with fever impaired cognition (Agitation, delirium, coma) muscle rigidity

Question 33

what is the treatment of NMS?

Answer 33

restore DA balance d/c drug use DA receptor agonist, diazepam, or dantrolene

Question 34

what is the MOA of atypical antipsychotics?

Answer 34

some activity as D2 antagonist in the mesolimbic system also acts as 5HT2a antagonists

Question 35

what are the clinical features of atypical antipsychotics?

Answer 35

controls positive symptoms (psychosis, bipolar, depression) and sometimes better management of negative symptoms lower risk of EPS some metabolic problems (weight gain, diabetes)

Question 36

what drugs are atypical antipsychotics?

Answer 36

clozapine, olanzapine, quetipaine, asenapine risperidone, ziprasidone, lurasidone aripiprazole pimavanserin

Question 37

why do atypical antipsychotics have a lower risk of EPS?

Answer 37

presynaptic 5HT2a receptors on DA neurons projecting from the SNpc to the striatum play a key role typical -- blocks POST synaptic

Question 38

what are the clinical features of clozapine (clozaril)?

Answer 38

1st atypical antipsychotic drug high efficacy especially for positive symptoms, but also for some negative symptoms lower D2 potency, so reduced risk of EPS

Question 39

what is the SE profile of clozapine (clozaril)?

Answer 39

anticholinergic, sedation, and orthostatic hypotension metabolic -- weight gain, risk of DM agranulocytosis

Question 40

what is agranulocytosis?

Answer 40

serious SE of clozapine involving a drop in neutrophil counts occurs in 1-2% of individuals within 6 months weekly blood monitoring is needed

Question 41

what are the clinical features of olanzapine (zyprexa)?

Answer 41

similar to clozapine with similar SE but usually less severe (no agranulocytosis)

Question 42

what are the clinical features of quetiapine (seroquel)?

Answer 42

similar to clozapine/olanzapine antagonizes D2, 5HT2a with a low risk of EPS same SE as olanzapine low antimuscarinic activity

Question 43

what atypical antipsychotics are most likely to experience SE?

Answer 43

clozapine = olanzapine > quetiapine = risperidone asenapine > ziprasidone = lurasidone = aripiprazole

Question 44

what are the clinical features of risperidone (risperidol)?

Answer 44

rationally designed to be a combined D2 and 5HT2a antagonist with low risk of EPS SE similar to quetiapine with low antimuscarinic activity

Question 45

what are the clinical features of ziprasidone (geodon/zeldox) and lurasidone (latuda)?

Answer 45

similar to risperidone but usually less severe

Question 46

what are the clinical features of aripiprazole (abilify)?

Answer 46

high affinity for D2/D3, but also acts as 5HT2a antagonist low risk of EPS with SE similar to ziprasidone low risk of weight gain, risk of diabetes

Question 47

how does aripiprazole act on the D2 receptor?

Answer 47

acts as partial agonist so that drug action varies with the level of DA in different brain regions

Question 48

how does aripiprazole act when DA is high?

Answer 48

lowers the DA response, but only to an intermediate level used in the limbic system of schizophrenia pts reduces positive systems in the limbic system

Question 49

how does aripiprazole act when DA levels are low?

Answer 49

increases the DA response to the same intermediate level works in the striatum or cortex of schizophrenia pts by staying in normal range in striatum, reduces risk of EPS in the cortex, reduces negative symtpoms

Question 50

what are the clinical features of pimavanserin (nuplazid)?

Answer 50

inverse agonist targeting 5HT2a used to reduce PD psychosis, including hallucinations and delusion created by DA treatments (L-DOPA or DA receptor agonists)

Question 51

what is cobenfy (KarXT)?

Answer 51

first ever approved schizophrenia drug that doesn't target the D2 receptor