Block 4 Lecture 4 -- Antipsychotics Flashcards by Drew Spargo

What is the general MoA of FGAs?

competitive, postsynaptic ML system D2r antagonists

– induce time-dependent change in DA neurotransmission

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What are the low potency FGAs?

1) chlorpromazine
2) prochlorperazine
3) thioridazine

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What are the high potency FGAs?

1) fluphenazine
2) haloperidol
3) pimozide
4) thiothixine

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What are the phases of FGAs effect on DA neurotransmission?

1) initial D2 blockade
2) continued D2 blockade
3) supersensitivity

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What happens in the initial D2r blockade by FGAs?

compensatory response

– increased DA synthesis and release

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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

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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

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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

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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

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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

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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)

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What are the antihistaminergic ADRs of FGAs?

due to H1 antagonism

- weight gain
- drowsiness

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What are the antiadrenergic ADRs of FGAs?

due to a1 antagonism

- orthostasis
- reflex tachycardia
- dizziness
- drowsiness

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What causes the anticholinergic ADRs of FGAs?

antagonism of M1

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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

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What type of receptor is M1? a1? H1?

all Gq

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What are special ADRs of chlorpromazine?

sedation
photosensitivity
jaundice

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What is the t1/2 of chlorpromazine?

30+ hours

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What are specific PK parameters for prochlorperazine?

t1/2 = 4-8 hrs

99% PPB

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What is the t1/2 of thioridazine?

30 hours

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What are significant ADRs of thioridazine?

very anticholinergic
very sedative
lower potential for EPS

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What is the t1/2 of fluphenazine?

20+ hours

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What are significant ADRs of fluphenazine?

significant EPS

a little sedation

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What is the t1/2 of haloperidol?

24 hours

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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