Block 4 Lecture 4 -- Antipsychotics Flashcards
What is the general MoA of FGAs?
competitive, postsynaptic ML system D2r antagonists
– induce time-dependent change in DA neurotransmission
What are the low potency FGAs?
1) chlorpromazine
2) prochlorperazine
3) thioridazine
What are the high potency FGAs?
1) fluphenazine
2) haloperidol
3) pimozide
4) thiothixine
What are the phases of FGAs effect on DA neurotransmission?
1) initial D2 blockade
2) continued D2 blockade
3) supersensitivity
What happens in the initial D2r blockade by FGAs?
compensatory response
– increased DA synthesis and release
What happens in the continued D2r blockade phase caused by FGAs?
1) inactivation of dopaminergic neurons
2) depolarization blockade
- - reduced DA release in ML and NS
- - reduced positive sxs
What happens in the supersensitivity phase of the D2 blockade caused by FGAs?
1) DAr upregulation
2) supersensitive to DAr agonsits
- - increased risk for tardive dyskinesia
- - weeks to develop
- - can be irreversible
ADRs of FGAs.
1) EPS
2) anticholinergic
3) anti-adrenergic
4) antihistaminergic
5) QT prolongation
6) metabolic syndrome
7) drug-induced seizures
8) neuroleptic malignant syndrome
What are the sxs associated with neuroleptic malignant syndrome?
SHACkA after 24-72 h
- stiff (muscle rigidity)
- hot (fever)
- altered (mental status)
- CK elevation
- autonomic instability
How is neuroleptic malignant syndrome treated?
rare, potentially fatal
d/c drug x several weeks
– supportive treatment (dantrolene + bromocriptine)
change drug, titrate slowly to minimum dose
What are the drug interactions for FGAs?
1) smoking (decreased drug levels)
2) CNS depressants (potentiation)
- - no PPB displacement rxns
- - no significant effect on CYPs (exception: chlorpromazine and thioridazine, 2d6)
What are the antihistaminergic ADRs of FGAs?
due to H1 antagonism
- weight gain
- drowsiness
What are the antiadrenergic ADRs of FGAs?
due to a1 antagonism
- orthostasis
- reflex tachycardia
- dizziness
- drowsiness
What causes the anticholinergic ADRs of FGAs?
antagonism of M1
What are the EPS ADRs of FGAs?
caused by D1,2 antagonism
1) dystonia
2) akathisia
3) tremor/rigidity/bradykinesia
4) irreversible tardive dyskinesia
5) antiemetic
6) gynecomastia (males) and menstrual irregularity
What type of receptor is M1? a1? H1?
all Gq
What are special ADRs of chlorpromazine?
sedation
photosensitivity
jaundice
What is the t1/2 of chlorpromazine?
30+ hours
What are specific PK parameters for prochlorperazine?
t1/2 = 4-8 hrs
99% PPB
What is the t1/2 of thioridazine?
30 hours
What are significant ADRs of thioridazine?
very anticholinergic
very sedative
lower potential for EPS
What is the t1/2 of fluphenazine?
20+ hours
What are significant ADRs of fluphenazine?
significant EPS
a little sedation
What is the t1/2 of haloperidol?
24 hours
What are significant ADRs of haloperidol?
significant EPS
a little sedation
Which FGAs have additional indications?
pimozide only
- Tourette’s
- resistant tics
What is the t1/2 of pimozide?
55+ hours
What is significant about thiothixine?
sulfonamide
35+ hours t1/2
What is the general MoA of atypicals/SGAs?
competitive D2 and 5-HT receptor antagonists
What are the SGAs/atypicals?
1) asenapine
2) iloperidone
3) lurasidone
4) olanzipine
5) quetiapine
6) risperidone
7) paliperidone
8) ziprasidone
9) clozapine
10) aripiprazole
What are the general ADRs of SGAs?
1) weight gain
2) metabolic syndrome
- - myocarditis/ cardiomyopathy
3) QT prolongation
4) agranulocytosis
5) tardive dyskinesia
PK notes for asenapine:
t1/2 = 24h
95% PPB
CYP1A2
PK notes for iloperidone:
t1/2 = 18-33 h
95% PPB
CYP3A4 and 2D6
PK notes for lurasidone:
t1/2 = 18h
9-19% Fpo increased by food
CYP3A4
PK notes for olanzapine:
t1/2 = 33 hours
93% PPB
PK notes for quetiapine:
t1/2 = 7 h (a. met 9-12h)
83% PPB
CYP3A4 + 2D6
PK notes for risperidone:
t1/2 = 20 hours
CYP3A4
PK notes for paliperidone:
t1/2 = 23 hours
renal excretion (adjust)
PK notes for ziprasidone:
t1/2 = 7 hrs
PK notes for clozapine:
t1/2 = 6-26 hours
PK notes for aripiprazole:
t1/2 = 75+ hours
99% PPB
CYP3A4, 2D6
Which atypicals are indicated for bipolar disorder?
1) lurasidone
2) quetiapine
3) risperidone
4) palperidone
5) ziprasidone
6) clozapine
7) aripiprazole
all “-dones” except Ilo-
Which SGAs have other indications besides schizophrenia and bipolar disorder?
1) asenapine (acute mania)
2) risperidone (behavior problems in autism)
3) clozapine (borderline personality disorder, treatment-resistant schizophrenia)
Which atypicals are sedative?
1) olanzapine
2) quetiapine
Which atypicals are associated with weight gain?
1) olanzapine (25%!)
2) clozapine
3) risperidone
ADRs of iloperidone?
orthostasis
Counseling point for asenapine:
SL tabs
- no chewing/crushing/swallowing
- don’t eat/drink within 10 mins
ADRs of risperidone:
1) weight gain
2) tardive dyskinesia
3) NMS
4) black box: increased mortality in patients with dementia (don’t use in elderly)
Which atypicals can’t be used in dementia patients?
risperidone
ziprasidone
clozapine
– all black-box
ADRs of ziprasidone:
black box: increased mortality in patients with dementia
Black-box warnings for clozapine:
1) agranulocytosis
2) myocarditis
3) dose-related seizure risk
4) orthostasis
5) increased mortality in patients with dementia
but, not associated with EPS
Drug interactions for clozapine:
BZDs:
– hypotension, respiratory depression
cigarettes:
– increased metabolism
MoA of clozapine:
low D2 and high 5-HT2a receptor antagonist
When is clozapine especially useful?
1) alleviation of positive symptoms (superior efficacy)
2) negative cognitive sxs (superior)
3) hostility and suicidality (superior to FGAs)
MoA of aripiprazole:
partial D2 agonist
full 5HT2a antagonist
What antipsychotics are available as long-acting injectables?
1) haloperidol
2) fluphenazine
3) risperidone
4) olanzapine
5) palperidone
6) aripiprazole
When are long-acting injectables preferred?
poor adherence
dose-dependent ADRs
– minimize peak-trough
Describe symptoms resolution timelines for positive and negative sxs.
psychomotor: 1 week
hallucination: 2 weeks
delusions: 3+ weeks
negative: 16 weeks
Why might polypharmacy be used?
1) to target sxs
2) to improve cognitive ability during cross-taper
3) to counteract side effect
What are arguments against polypharmacy?
no sufficient evidence of benefit
- dose-related ADRs
- more risk for cognitive impairment
What drug is OFTEN augmented with another drug?
clozapine
- to reduce negative sxs
- take 10 weeks to observe benefit
What are the phases of therapy?
acute psychosis
stabilization
maintenance
What is the GoT in acute psychosis?
manage acute sxs
prevent threat to self
What is the GoT in stabilization
reduce ADRs
maintain compliance
What is the GoT in maintenance?
improve psychosocial functioning and QoL
prevent relapse
What SGAs have the least risk of weight gain?
ziprasidone, aripiprazole
How to manage the metabolic syndrome ADRs of SGAs?
change drug if 5% weight gain
– to avoid risk of T2DM
