Antipsychotics - Linger Flashcards
aripiprazole
atypical antipsychotic
lurasidone
atypical antipsychotic
olanzapine
atypical antipsychotic
quetiapine
atypical antipsychotic
risperidone
atypical antipsychotic
ziprasidone
atypical antipsychotic
clozapine
special use atypical antipsychotic
chlorpromazine
typical low potency antipsychotic
haloperidol
typical high potency antipsychotic
atypical
because dramatic reductionin extrapyramidal side effects
dopamine hypothesis
evidence for:
- antipsychotics - some block D2 receptors postsynaptic
- drugs increase DA - aggravate schizophrenia or trigger psychosis
- DA receptors - more in brain of schizophrenic
- post-mortem - more DA and D2 receptorrs in schizophrenic nucleus accumbens, caudate, putamen
evidence against:
- decreased cortex/hippocampus DA activity - underlie cognitive impairment and negative sx of schizophrenia
- many atypicals - lower affinity for D2 receptors - but effective for schizophrenia tx
dopamine hypothesis - oversimplification
serotonin hypothesis
hallucinogenics - LSD, mescalin
-serotonin receptor agonists
bio basis of schizophrenia
DA, serotonin, glutamate imbalance
glutamate hypothesis
low function NMDA receptors
- on GABA internerous
- induce disinhibition of glutamatergic activity - hyperstimulation
atypical antipsychotics
greater effect at 5-HT2a than D2 receptors
-dissociation of EPS and antipsychotic efficacy
phenothiazine derivative
chlorpromazine
aliphatic
more sedation and weight gain
butyrophenone derivative
haloperidol
high level of EPS
more potent, fewer autonomic effects
- but more EPS
- compared to phenothiazines
cholinergic rebound and withdrawal movement disorders
clozapine
cholinergic rebound
also with chlorpromazine and thioridazine
relapse to schizo after stop taking drug
most - 6 months
except - clozapine - rapid and severe relapse
efficacy of typical antipsychotics
D2 receptor affects
atypical antipsychotics
block 5-HT2A more potently than inhibit D2 receptors
mesolimbic mesocortical pathway
behavior and cognition
VTA - projection to limbic system and neocortex
inhibition of DA activity - antipsychotic effect
nigrostriatal pathway
coordination of movement
substantia nigra to dorsal striatum (caudate/putamen)
inhibit - EPS
tuberoinfundibular system
PRL release
DA inhibits
arcuate nucleus and periventricular neurons
-to hypothalamus and posterior pituitary
pathway inhibited by antipsychotics - PRL release
D1-like
D1 and D5
increase cAMP - activate Gs and adenylyl cyclase
D2-like
D2, D3, and D4
decreased cAMP - Gi - inhibit Ca channels, open K channels
D2 receptors
role in action of antipsychotics
D2 binding affinity
strong correlation with antipsychotic potency and EPS
typical antipsychotics
need 60% occupancy of striatal D2 receptors for antipsychotic
EPS at 80%
atypical antipsychotics
need 30-50% occupancy of striatal D2 receptors for antipsychotic
bc concurrent high occupancy at 5-HT2A receptors
aripiprazole
high D2 occupancy - without EPS
partial agonist at D2
catatonic schizo tx
benzos
reduce risk of suicide in schizoaffective pt
clpzapine
non-psych indications of antipsychotics
antiemetic
neuroleptanesthesia
first line tx of schizophrenia
atypical antipsychotics
-except clozapine and olanzapine
effective drug tx
both positive and negative sx improve
acute control uncoop patient
haloperidol
autonomic side effect
chlorpromazine
severe EPS
haloperidol
agranulocytosis
clozapine
lower seizure threshold
clozapine
QT prolongation
ziprasidone
dibenzothiazepine
quetiapine
dihydroindolone
ziprasidone
dihydrocarbostyril
aripiprazole
thienobenzodiazepine
olanzapine
benzisoxazole
risperidone
dibenzodiazepine
clozapine
butyrophenone
haloperidol
weight gain
olanzapine
atypicals
wide therapeutic index
adverse of clozapine
agranulocytosis and myocarditis
only patients refractory high dose other agents
-or suicidal
full effect of tx
16-20 weeks
electroconvulsive therapy
adjunct for tx of mood sx and positive sx
augment - clozapine - max dose of clozapine ineffective
anhedonia
inablity to experience pleasure
akathisia
uncontrolled restlessness - can’t sit still
tx of EPS
anticholinergic
antimuscarinic (antihistamine - diphenhydramine)
early motor effects antipsychotics
EPS - 1-3 days
parkinsonism, increased activity
akathisia - can’t sit still
acute dystonic rxns
EPS and dystoni tx - anticholinergic or antihistamine
never use levodopa in these patients
later motor effects of antipsychotics
tardive dyskinesia
with chronic tx - months/years
writhing movements of tongue, face body - choreoathetoid
imbalance of cholinergic vs. dopaminergic activity in motor pathways
lower risk of tardive dyskinesia
clozapine or quetiapine
seizure threshold
lowered with most antipsychotics
clozapine - seizures in 2-5% of patients
typical antipsychotics
affinity for muscarinic cholinergic and a1 adrenergic receptors
anti-PS effect
loss of accomodation, dry mouth, difficulty urinating, constipation
orthostatis hypotension, dizzy, sedated, impotent, failure to ejaculate
switch to newer typical agent
high risk of weight gain
clozapine
olanzapine
intermediate risk of weight gain
iloperidone
paliperidone
quetiapine
risperidon
low risk weight gain
asenapine
lowest risk of weight gain
lurasidone
aripiprazole
ziprasidone
weight gain
follow food intake, BMI, blood sugars, and lipids
hyperglycemia and hyperlipidemia common problems
hyperPRL
with antipsychotic use
loss of DA inhibition of PRL secretion
amenorrhea-galactorrhea, infertile, osteoporosis - women
infertility, loss of libido, impotent, gynecomastia - men
more with older typical antipsychotics
-as well as risperidone and paliperidone
agranulocytosis
with clozapine
need to monitor CBC
- weekly first 6 months
- every 3 weeks thereafter
QT prolongation
with several antipsychotics
risk sudden death
avoid antiarrhythmics and erythromycin (prolong QT)
antipsychotics in pregnancy
atypical preferred
considered relatively safe - category C
neuroleptic malignant syndrome
life-threatening acute severe parkinsonism, muscle rigid, autonomic instability, HTN, hyperthermia, stress leukocytosis (infection misdiagnosis)
side effect of antipsychotics
tx - supportive - cool body, muscle relaxants
positive sx
excess DA - mesolimbic system
negative sx
loss of DA - mesolimbic system
dopamine receptors
GPCRs
typical vs atypical
typical - positive sx treatment
atypical - positive/negative sx treatment
loss of accomodation, dry mouth, difficulty urinating, constipation
muscarinic cholinoceptor blockade
orthostatic hypotension, dizzy, sedation, failure to ejaculate
a-adrenoreceptor blockade
parkinsons syndrome, akathisia, dystonia
dopamine receptor blockade
weight gain
combined H1 and 5-HT2 blockade
endocrine changes
dopamine receptor blockade
acute motor effects
D2 blockade basal ganglia - EPS
treatable
late onset motor effects
tardive dyskinesia
imbalance - cholinergic deficiency and dopaminergic supersensitivity
may be irreversible
tx tardive dyskinesia
decrease dose - initially get worse - improve over weeks
switch - quetiapine or clozapine
more severe with haloperidol
EPS
chlorpromazine
has activity at many receptors
so get unwanted effects
cholinergic, a-adrenergic, H1
low potent at D2
tx bipolar depression
aripiprazole
less weight gain and hyperglycemia
olanzapine
bind 5-HT2a, Ma, and H1 high affinity
severe weight gain
aripiprazole
partial D2 agonist
lurasidone
tx schizo and bipolar
D2 and 5-HT2 - high affinity
no QT prolongation
quetiapine
low affinity D2 and 5-HT2
higher affinity H1 and alpha1 - sedation and orthostatic
off label use as sleep aid
QT prolongation - poor choice for those with heart issue
risperidone
high affinity 5-HT2a, D2 and alpha1
highest EPS and hyperPRL
floppy iris syndrome before cataract surgery
ziprasidone
high affinity 5-HT2a - lower affinity D2
CI - patient with recent MI - QT prolongation
antiemesis
DA blockade
neuroleptanesthesia
analgesia and amnesia
droperidol
fetanyil
nitrous oxide
