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