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Pharm (Geisel M2) > Term 2 Pharm - Anti-Psychotics > Flashcards

Term 2 Pharm - Anti-Psychotics Flashcards

1
Q

Psychotic Disorders

A 
Schizophrenia
Schizoaffective, Schizophreniform, Delusional Disorder
Bipolar Disorder with Psychosis
Major Depression with Psychosis
Other – e.g., substance induced, etc.
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2
Q

Domains of Schizophrenia (4)

A

Positive Symptoms
Negative Symptoms
Disorganization
Cognitive Function

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3
Q

Suicide and Schizophrenia

A

Suicide attempts = 20 – 40% of schizophrenic population

Rate of suicide = 10% (20 – 50 times general population)

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4
Q

Relationship of Schizophrenia to substance abuse

A

Lifetime prevalence - 47% of Patients have Any Comorbid Substance Use Disorder in Lifetime

Substance abuse makes this disorder worse but helps reward system so makes ppl feel better although making disease worse

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5
Q

What type of problems does Schizophrenia cause

A

Schizophrenia is a multiple system disorder ppl die 28.5 years earlier than everyone else (a lot tied with cardiovascular problems)

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6
Q

Current Models of Schizophrenia

A

2 implications for treatment:

  • Neurodevelopmental
  • Neurodegenerative

Neurodevelopmental - an abnormality of some sort occurs early in life (maybe in utero on temporal lobes silent effects until puberty… negative symptoms are primary & psychosis is secondary)

Neurodegenerative – possible glutamate abnormalities? Possible explanation for life shortening? Do anti-psychotics have life shortening effects

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7
Q

Neurodevelopmental Model

A
  • Early abnormality (primarily temporal?)
  • Development of hypofrontality
  • Subsequent mesolimbic hyperactivity
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8
Q

Mesocorticolimbic Dopamine System

A

(see slide 10)

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9
Q

Neurodegenerative Model (Causes of psychosis)

A
  • PCP (phencyclidine) and psychosis
  • NMDA antagonists produce positive and negative symptoms and cognitive deficits
  • Glutamatergic dysregulation leads to apoptosis?
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10
Q

What do All Treatments for Psychotic Disorders do?

A

They ALL block D2 receptor (Dopamine)

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11
Q

Typical antipsychotics

A
  • Chlorpromazine
  • Haloperidol Fluphenazine
  • Thioridazine
  • Loxapine
  • Perphenazine
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12
Q

Atypical (novel) antipsychotics

A
  • Clozapine*
  • Risperidone
  • Olanzapine*
  • Quetiapine
  • Ziprasidone
  • Aripiprazole*
  • Paliperidone
  • Iloperidone
  • Asenapine
  • Lurasidone
  • Brexpiprazole
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13
Q

Development of Typical Antipsychotics

A
  • Chlorpromazine discovered by serendipity
  • Other typical antipsychotics discovered based on effects on movement in animal models
  • Importance of blockade of DA D2 receptors recognized later – 2000 Nobel Prize to Arvid Carlsson
  • ALL “first-generation” antipsychotics cause extrapyramidal symptoms (EPS)
  • high potency results in HIGH EPS

(Blocking dopamine receptors can result in rigidity/tremor)

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14
Q

Typical Antipsychotics (Neuroleptics)

A

Chlorpromazine (Thorazine)——– low potency

Perphenazine (Trilafon) ———–mid range

Haloperidol (Haldol) —————high potency
Fluphenazine (Prolixin) ———–high potency

(low potency drugs) Have Anti-cholinergic effects Less parkinsons/rigidity symptoms

High potency drugs do not have anti-Ach so it comes with more parkinsons/rigidity symptoms

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15
Q

Dopamine Hypothesis of Schizophrenia

A

Hypoactivity (Mesocortical pathway) = negative symptoms

Hyperactivity (mesolimbic pathway) = positive symptoms

ALL drugs inhibit prolactin (Tuberoinfundibular pathway)

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16
Q

Effect of Typical Antipsychotics

A

Days – calm behavior, improve sleep, decrease confusion.
Days – weeks – decrease psychotic symptoms
Weeks – months – improve insight?
Negative symptom improvement minimal
Cognitive improvement usually minimal
Disability may remain

Huge problem with SCZ is problems with insight

17
Q

Side Effects of Typical Antipsychotics

A

Low potency

  • Dry mouth, blurred vision, constipation, urinary retention, hypotension, sedation, weight gain
  • Less acute dystonia, NMS
  • Parkinsonism, akathesia, tardive dyskinesia
  • Prolactin elevation

High potency

  • More acute dystonia, NMS
  • Parkinsonism, akathesia, tardive dyskinesia
  • Prolactin elevation
Akathesia = restlessness, busy body 
Tardive dyskinesia (from blockage of D2 receptor, increase activity of DA 
Treat dystonia with an anticholinergic
18
Q

Diagnosis of Neuroleptic Malignant Syndrome

A

Minor Manifestations

  • Tachycardia
  • Abnormal blood pressure
  • Tachypnea
  • Altered consciousness
  • Diaphoresis

Major Manifestations

  • Fever
  • Rigidity
  • Elevated CPK level

Diagnosed when: three major OR two major and four minor

19
Q

Typical Outcomes of Antipsychotics

A
  • Limited clinical efficacy
  • Relapses common
  • Cognitive deficits continue
  • Substance use common
  • Neurological side effects
20
Q

Novel (atypical) antipsychotic drugs

A
  • clozapine*
  • risperidone (and risperidone long-acting)
  • olanzapine* (and olanzapine pamoate)
  • quetiapine
  • ziprasidone
  • aripiprazole* (and aripiprazole long-acting)
  • paliperidone (and paliperidone palmitate)
  • iloperidone
  • asenapine
  • lurasidone
  • brexpiprazole
  • Less EPS
  • Less prolactin elevation (except risperidone, paliperidone)
  • Releases dopamine in prefrontal cortex
  • Weight gain (MOSTLY in Clozapine)
21
Q

Novel Antipsychotics Potential Benefits

A

Improved efficacy?
Fewer relapses?
Fewer neurological side effects
Useful in affective psychosis
Role in suicidal patients – clozapine data
Role in comorbid substance use – clozapine data

22
Q

Clozapine*

An Atypical Antipsychotic Drug

A
  • Introduced over 30 years ago (chemical relative of loxapine), and seen to be effective.
  • Caused agranulocytosis (decrease in WBCs, can use, but monitor the WBC count)
  • Withdrawn from the market in mid-1970’s.
  • Relative safety/efficacy demonstrated in 1988.
  • Re-introduced as treatment for treatment for resistant schizophrenia in 1989.

Dramatically effective for positive and some negative symptoms.
Minimal EPS effects.
Minimal prolactin elevation.

Weak DA D2 receptor antagonism; potent antagonism at 5HT2 and NE α2 receptors

23
Q

Clozapine Side Effects

A 
Agranulocytosis
Seizures
Myocarditis
Weight gain, glucose and lipid dysregulation 
Tachycardia, hypotension
Drooling
Sedation
Liver function changes
24
Q

Clozapine vs. olanzapine

Response of Suicidality

A

Clozapine vs. olanzapine: decreased time to hospitalization to prevent suicide or to a suicide attempt

25
Q

Risperidone

A
  • First post-clozapine atypical antipsychotic; 5HT2/D2 ratio similar to clozapine
  • Fewer relapses than haloperidol
  • Side effects: EPS (higher doses), prolactin elevation
26
Q

Olanzapine*

A
  • Second post clozapine novel antipsychotic
    5HT/D2 receptor blockade similar to clozapine
  • Low EPS, low prolactin elevation
  • Side effects: weight gain, glucose/lipid dysregulation?, sedation
27
Q

Quetiapine = Seroquil

A
  • 5HT/D2 ratio receptor blockade similar to clozapine
  • Few serious side effects
  • Minimal EPS
  • Minimal prolactin elevation
  • Cataract warning (animal studies)
28
Q

Aripiprazole*

A
  • Partial dopamine agonist
  • Minimal EPS, no prolactin elevation, low weight gain.
  • Early activation, insomnia

Can be used as a regulator
If system is over active – brings it down
If system is underactive – brings it up

29
Q

CATIE Phase I

Double-Blinded and Randomized Study done to see how many people have to stop treatment b/c of adverse effects

A

Olanzapine was best (had fewest ppl discontinue) –> but had the most weight gain

30
Q

Potential Role of Noradrenergic Activity in Action of Clozapine

A

Clozapine treatment associated with dramatic increase in plasma norepinephrine

In animal models, α2 antagonists increase efficiency of firing patterns in DA neurons in mesocorticolimbic circuits

Noradrenergic effects coupled with potent 5-HT2 and weak D2 antagonism could be linked to actions of clozapine

31
Q

Cardinal Rule

A

Also NEVER abruptly stop any antipsychotic drug

32
Q

Aripiprazole*

A

Aripiprazole is a high-affinity D2 partial agonist
- Functional antagonist under conditions of dopamine hyperactivity
- Functional agonist in conditions of
dopamine hypoactivity

33
Q

Amphetamine induced psychosis

A

All typical and atypical antipsychotics are blockers of the dopamine D2 receptor

34
Q

PCP induced psychosis

A

Glutamate model of psychosis

35
Q

Glutamatergic System

A

NMDA receptors
KA receptors
AMPA receptors

Metabotropic receptors – mGluR (1 – 8)

36
Q

D-Cycloserine

A
  • Partial agonist at glycine modulatory site
  • When added to typical antipsychotic, modest decrease in negative symptoms
  • When added to CLOZ, no effect or increased symptoms (b/c it has some of same effects)
37
Q

Metabotropic Receptor (mGluR) Modulators

A

Group 2/3 metabotropic agents are negatively linked to glutamate release – limit endogenous release under conditions of glutamate excess

38
Q

Beyond psychosis: Other uses of “antipsychotic” drugs

A

Bipolar disorder, psychotic depression

Personality disorders?

Treatment resistant depression (as adjunctive treatment)

Pharm (Geisel M2) (15 decks)

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